Molecular and Translational Classifications of DAMPs in Immunogenic Cell Death

Abstract

The immunogenicity of malignant cells has recently been acknowledged as a critical determinant of efficacy in cancer therapy. Thus, besides developing direct immunostimulatory regimens, including dendritic cell-based vaccines, checkpoint-blocking therapies, and adoptive T-cell transfer, researchers have started to focus on the overall immunobiology of neoplastic cells. It is now clear that cancer cells can succumb to some anticancer therapies by undergoing a peculiar form of cell death that is characterized by an increased immunogenic potential, owing to the emission of the so-called “damage-associated molecular patterns” (DAMPs). The emission of DAMPs and other immunostimulatory factors by cells succumbing to immunogenic cell death (ICD) favors the establishment of a productive interface with the immune system. This results in the elicitation of tumor-targeting immune responses associated with the elimination of residual, treatment-resistant cancer cells, as well as with the establishment of immunological memory. Although ICD has been characterized with increased precision since its discovery, several questions remain to be addressed. Here, we summarize and tabulate the main molecular, immunological, preclinical, and clinical aspects of ICD, in an attempt to capture the essence of this phenomenon, and identify future challenges for this rapidly expanding field of investigation.

Introduction and Historical Background

Augmenting the immunogenicity of cancer cells to improve the efficacy of cancer therapy is a paradigm that has gained significant momentum over the past 5 years (1–5). Researchers have realized that besides therapeutically exploiting innate or adaptive immune cells directly (e.g., through dendritic cell (DC)-based vaccines or adoptive T-cell transfer) and/or improving the effector functions of T cells (through checkpoint-blocking therapies), cancer cells also need to be made immunogenic (1, 4, 6, 7). This has diverted attention toward studying the interface between stressed or dying cancer cells and the immune system, in the hope of efficiently exploiting it for therapeutic purposes (1).

Early indications regarding immune system-driven tumor control emerged in the eighteenth century, when feverish infections in cancer patients were circumstantially associated with tumor remission (8). The first evidence that immunotherapy can be applied to achieve tumor regression emerged from the work of William Coley, who in the 1890s achieved tumor regression in some sarcoma/lymphoma patients upon the intra-tumoral injection of streptococcal cultures (provided by Robert Koch) (8, 9). In the following 43 years, Coley injected nearly 900 (mostly sarcoma) patients with his bacterial preparation (achieving a cure rate >10%), which later became known as “Coley’s toxin” (8, 10). However, the Coley’s toxin came under intense scrutiny owing to an elevated toxicity and some difficulties in reproducing remission rates (8). Eventually, the first experimental evidence that virus-unrelated tumors can indeed be recognized by the host immune system emerged in the 1940s, and by the 1960s, coupled with the discovery of T cells, it was proposed that the human immune system may also react against tumors (11). The ability of anticancer therapies to enhance the immunogenic potential of malignant cells gained some appreciation by the 1970s (12–14). It was recognized that if specific treatments are applied (e.g., radiotherapy, the bacillus Calmette–Guerin, or some chemotherapeutics), the immunogenicity of malignant cells increases enough to induce durable anti-tumor immunity (12–14). By the 1980s, researchers started to report more specific observations regarding the therapeutic impact of cancer cell immunogenicity, e.g., the ability of curative hyperthermia to cause the (heat-shock based) generation of circumstantial anti-tumor immunity (15), the fact that the immunogenicity of cancer cells influences patient prognosis after radiotherapy (16), and the increase in tumor immunogenicity due to hydrostatic pressure (17). However, these early studies (especially those published before the 1980s) had several issues linked to a lack in consensus. For instance, due to early controversies on the existence of tumor-associated antigens (TAAs) (11), the target of tumor-specific immune responses was unclear, and the mechanism of action of some therapies came under scrutiny. Moreover, such therapies could operate by directly modulating immune effector cells rather than improving the immunogenic potential of tumors (18). In particular, the death of cancer cells exposed to therapy was never suspected to drive anti-tumor immunity, since it was considered to be a relatively “silent” process in terms of immunogenicity (19). Moreover, the classical “self/non-self” theory was unable to explain the possibility that dying cancer cells could elicit an immune response (20).

By the early 1990s, the molecular characterization of mice and human TAAs clarified the entities targeted by anti-tumor immune responses (11). Similarly, the so-called “danger theory” started to emerge, challenging the classical model of “self/non-self” immune recognition, especially in a diseased or damaged tissue (20, 21). This model proposed that the immune recognition is not restricted to “non-self” entities, but rather discriminates between “dangerous” and “safe” entities, irrespective of source (20–22). Indeed, “dangerous” entities include pathogens as well as injured, infected, diseased and necrotic tissues, or cells undergoing non-physiological cell death which emit danger signals (or alarmins) with pro-inflammatory activity (21, 22). These danger signals are now collectively referred to as “damage-associated molecular patterns” (DAMPs) (23). DAMPs are endogenous molecules that are concealed intracellularly in normal conditions, but are exposed or released upon stress, injury, cell death, thereby becoming able to bind cognate receptors on immune cells (3, 24–27). Table 1 summarizes the most prominent DAMPs characterized to date and their mode of emission, the cell death pathway they are associated with, and their known cognate receptors. It is important to consider that not all DAMPs may act as immunogenic danger signals. Several DAMPs exist that are crucial for the maintenance of tissue homeostasis, and the avoidance of auto-immune responses, as they exert immunosuppressive effects, including phosphatidylserine (PS), annexin A1 (ANXA1), death domain 1α (DD1α), B-cell CLL/lymphoma 2 (BCL2) and some extracellular matrix-derived molecules (Table 1). Accordingly, the blockade of these anti-inflammatory DAMPs accentuates the immunogenic potential of dying cells, or renders immunogenic otherwise tolerogenic forms of cell death (28, 29). Moreover, some danger signals are not always involved in the immunogenicity of cell death, but act as “bystanders.” This is the case for heat shock protein 90 kDa alpha (cytosolic), class A member 1 (HSP90AA1, best known as HSP90) exposed on the cell surface after melphalan treatment (30). Last (but not least), several DAMPs may be subjected to post-translational modifications (e.g., oxidation, reduction, citrullination) that may potentially neutralize, increase, or change their immunogenic properties (31, 32) – a process that is still incompletely understood.

Despite these advances, the overall role of regulated cell death (RCD) (97) in augmenting cancer immunogenicity remained obscure. Initial observations involving the immunogenicity of cell death in the efficacy of cancer therapy were published between 1998 and 2004, when it was proposed that the non-apoptotic demise of malignant cells (within the context of the so-called “immunogenic death”) could be associated with the emission of the danger signal heat shock 70 kDa protein 1A (HSPA1A, best known as HSP70) (Table 1), enhancing the immunogenic potential of dying cancer cells in vivo (98, 99). The dogmatic view that only necrotic or non-apoptotic (as postulated by the “immunogenic death” concept) cancer cells are characterized by an elevated immunogenic potential started to be questioned by a series of studies published between 2005 and 2007 (41, 70, 100, 101). These publications outlined that cancer cells undergoing apoptosis in response to specific anticancer therapies are immunogenic [a subroutine termed immunogenic cell death (ICD)], as long as they emit precise DAMPs in a spatiotemporally defined fashion (26, 102, 103). Cells succumbing to ICD are sufficient for the elicitation of durable anti-tumor immune responses (1, 26, 53, 102, 104). ICD is indeed paralleled by the redirection and emission of DAMPs, owing to the stimulation of distinct danger signaling pathways occurring in synchrony with cell death signaling (103). Table 2 summarizes the main signaling pathways that play a role in the trafficking and emission of DAMPs. ICD-associated DAMPs and other immunostimulatory factors released by cells destined to undergo ICD favor the establishment of a productive interface between dying cancer cells and innate immune cells (like DCs or macrophages), thereby leading to the initiation of a therapeutically relevant adaptive immune response (Figure 1) (102, 105). In some contexts, DAMPs may regulate the function of specific innate immune cell subsets, e.g., following anthracycline treatment, extracellular adenosine triphosphate (ATP) assists in recruitment and differentiation of CD11c⁺Cd11b⁺Ly6C^high cells into CD11c⁺CD86⁺MHCII⁺ DCs (106); similarly, necrosis associated F-actin exposure activates an immune response by directing the dead cell debris to specifically CD8α⁺ DCs (59, 107). Indeed, DCs and other antigen-presenting cells exposed to cancer cells succumbing to ICD can then prime CD4⁺ T cells (and polarize them into T_H1, T_H17, or T_H1/T_H17-like phenotype), CD8⁺ cytotoxic T lymphocytes (CTLs) and γδ T lymphocytes against one or several TAAs (Figure 1) (102). Of note, residual cancer cells that survive ICD inducers can also show some enduring immunogenic characteristics that make them susceptible to immunological control by CTLs (108–110).

Figure 1

Immunogenic Cell Death Inducers

Over the past few years, a number of single-agent ICD inducers have been discovered, encompassing conventional chemotherapeutics, targeted anticancer agents and various other ­biological and physicochemical therapies (18, 102, 104, 127). Table 3 summarizes single-agent ICD inducers characterized so far, as per consensus guidelines (104), and the spectra of DAMPs and other immunostimulatory signals associated with them. For combinatorial therapeutic strategies capable of achieving ICD, readers may want to refer to other recent publications (18, 128, 129). It is clear that a general structure–function relationship capable of clustering all existing ICD inducers and predicting new ones does not exist (130), an issue that makes discovering new ICD-inducing therapies based on cheminformatic analyses challenging, if not impossible. A peculiar characteristic of most, if not all, ICD inducers is their ability to induce reactive oxygen species (ROS)-based/associated endoplasmic reticulum (ER) stress, as first delineated for anthracyclines (30, 34, 35, 42, 123, 131–133). This peculiarity was exploited for the targeted discovery of hypericin-based photodynamic therapy (Hyp-PDT) – a therapeutic modality that can trigger ICD through the induction of ROS that target the ER (35, 116, 134). Along with an ever more precise characterization of the links between ROS, ER stress, and ICD induction (135, 136), it became clear that the more “focused” ER stress is, the higher the probability of inducing ICD (3, 26, 53, 137). These observations paved way for a classification system based on how ICD inducers engage ER stress for cell death and danger signaling (3, 26, 53, 138). Based on this classification, Type I ICD inducers are defined as anticancer agents that act on non-ER proteins for the induction of cell death, but promote collateral ER stress for danger signaling, thereby operating on multiple targets (3, 26, 53), while Type II ICD inducers are anticancer agents that target the ER for both cell death induction and danger signaling (3, 26, 53). Table 4 summarizes the classification of current ICD inducers into Type I and Type II, and their cell death/danger signaling targets. Such a classification suggest that while Type I ICD inducers can be discovered through various approaches (e.g., DAMP-based drug screening platforms) (130, 139), putative Type II ICD inducers can be characterized rapidly on the basis of their ability to selectively or predominantly target the ER. Recent findings comforted the purpose and usefulness of this classification system, as two novel Type II ICD inducers [i.e., Pt^II N-heterocyclic carbene complex (140) and Newcastle disease virotherapy (NDV) (43)] were identified based on the notion that they induce predominant ROS-based ER stress (138). Nevertheless, as more ICD inducers and features are discovered, this classification system is expected to evolve or be substituted by a more refined one.

Since its discovery, a plethora of molecular and immunological components responsible for ICD have been discovered (Figure 1) (26, 102, 188). Table 5 summarizes the molecular and immunological determinants of ICD characterized so far, as well as the models of ICD in which they operate (in a positive, negative or dispensable manner). Anthracyclines and oxaliplatin are the most common ICD inducers employed in experimental settings, followed by Hyp-PDT. According to current understanding, cancer cell-associated determinants of ICD can be subdivided into those that are common to all ICD inducers (i.e., “core” signaling components), and those that operate in an ICD inducer-dependent manner (i.e., “private” signaling components) (26, 189). Thus, eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3, best known as PERK) and the ER-to-Golgi secretory machinery are considered “core” signaling components on the cancer cell side (26, 102). Similarly, from the immune system side, a general role for (IFNγ-producing) CD4⁺ and CD8⁺ T cells has been confirmed for most, if not all, ICD inducers (Table 5). Interestingly, some components that are required for ICD induction by some agents (like autophagy for anthracyclines and oxaliplatin) (190) might be either dispensable for ICD induction by other agents, e.g., autophagy for NDV (43) and phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), caspase-8 (CASP8) activation or cytosolic Ca²⁺ levels for Hyp-PDT (35); or even negatively regulate ICD in some settings, e.g., autophagy in case of Hyp-PDT (34) (Table 5). Thus, it will be important to expand our molecular knowledge of ICD to as many experimental settings as possible.

Immunogenic Cell Death from Bench to Bedside

The relevance of ICD has been verified in a number of rodent models, with a variety of chemical and physicochemical ICD inducers (26, 102). Table 6 summarizes the most prominent mouse or rat models used so far for the characterization and study of ICD. For the moment, ICD has been mostly investigated in heterotopic syngeneic subcutaneous models (195). Within such models, inter-species differences (mouse versus rats), inter-strain differences (among BALB/c, C57BL/6, C3H and KMF mice), and inter-cell line differences, as well as differences in therapeutic setups (prophylactic versus curative) have been amply accounted for (Table 6). Nevertheless, there is predominance in the use of cancer cells derived from carcinogen-induced tumors and transplanted subcutaneously (Table 6). In very few cases, ICD has been characterized in either orthotopic (for NDV) or spontaneous (for anthracyclines) tumor murine models (Table 6). This has been questioned as a prominent Achilles’ heel of ICD research (195). While this criticism is valid, it has to be recognized that no rodent model is perfect at all immunological levels (196).

As a recent systematic review summarized (196), heterotopic murine models suffer from a number of caveats, including the inability to recapitulate the early interaction between transformed cells and the immune system and the incompatibility between the cancer type and the site-of-transplantation (196). Orthotopic murine models are useful as they overcome the cancer cell-tissue type incompatibility issue (196). While genetically engineered tumor murine models (GEMMs) overcome most of the issues mentioned above, they come with their own set of shortcomings, including a limited genetic mosaicism, a low tumor heterogeneity, a lack of well-defined immunogenic TAAs, the presence of unintended “passenger” genetic modifications, and a reduced mutational spectrum (196). Many of these parameters are critical for responses to immunotherapy/ICD. For instance, the lack of well-defined immunogenic TAAs was the reason why preliminary results obtained in spontaneously developing murine tumors disputed the very existence of TAAs (11). Similarly, a high mutational spectrum (which produces considerable amounts of neo-antigens) has been found to be mandatory for the clinical efficacy of checkpoint blockers (209). Last (but not least), laboratory rodent models in general are associated with some critical issues, including the fact that a high level of inbreeding (which produces a number of shortcomings e.g., homozygous recessive defects) reduces the general immunological fitness, responsiveness and diversity in these models (196, 210, 211). Moreover, numerous immunological differences between mouse and humans tend to affect the translational relevance of the findings obtained (26, 211, 212). Also, the time frames of tumor growth rates between rodent models and humans are relatively divergent (196, 213, 214). This further complicates clinical translation of immunotherapeutic paradigms since the level of immunosurveillance and immunoediting experienced by human tumors can be much higher than any rodent tumor model.

In summary, it would be ideal to test ICD across as many different rodent models as possible, in order to determine the features that can be exploited for therapeutic purposes in humans. Moreover, if ICD fails in a specific experimental model, active effort should be made to characterize the mechanisms behind such failure, since resistance phenotypes can have profound clinical implications. This emerges from various studies summarized in Table 7. Indeed, several ICD resistance mechanisms exist operating at both the cancer cell and the immune system level, which have been characterized in different experimental models. Several of these resistance mechanisms have also been identified in cancer patients, thereby justifying further studies along these lines Table 7.

A considerable amounts of clinical findings support the relevance of ICD or ICD-related signatures in (at least subsets of) cancer patients. As summarized in Table 8, various ICD-linked (specific) parameters have been associated with the prognosis of cancer patients treated with clinically relevant ICD inducers (like anthracyclines, oxaliplatin, paclitaxel, or radiotherapy). Moreover, it is becoming clear that ICD-related or ICD-derived (immunological) genetic signatures (e.g., a MX1-centered metagene, a CXCR3-PRF1-CASP1-centered metagene, an ASAH1-centered metagene) can be positively associated with good prognosis in patients affected by various neoplasms, including breast, lung, and ovarian malignancies (141, 188, 220). These observations indicate that ICD or ICD-relevant parameters may have prognostic or predictive relevance in at least a subset of cancer patients. It will be important to characterize new and more specific ICD-associated parameters linked to patient prognosis as well as biomarkers that may predict improved disease outcome in cancer patient treated with ICD inducers. Of note, considering the current clinical experience with immunotherapies (209, 221), the patients with an increased likelihood to benefit from ICD inducers are probably those that display pre-existing (baseline) immune reactivity against cancer cells (220, 222, 223). This may depend on the ability of ICD to reboot and/or revive pre-existing TAA-directed immunity rather to prime de novo immune reactivity (5, 191, 224). In future, it would be crucial to characterize biomarkers that allow clinicians to delineate patients with reduced baseline immune reactivity against malignant cells so that proper combinatorial therapies involving ICD inducers can be implemented.

Confronting the Clinical Realities of Anti-Tumor Immunity

It is well-established that the response of cancer patients to immunotherapy relies on the activity of effector T cells [that employ their T-cell receptors (TCRs) for recognizing TAAs]. However, these TAA-targeting T cells may also constitute obstacles for effective anti-tumor immunity (234). As opposed to T lymphocytes recognizing pathogen-associated antigens (PAAs) (Figure 2), indeed, T cells directed against some TAAs (derived from non-mutated proteins that are source of self or near-to-self antigens) are developmentally subjected to negative selection in the thymus and peripheral lymphoid organs (234, 235) (Figure 2). As a result, T cells bearing TCRs with high affinity for self antigens (including some TAAs) are clonally deleted to avoid auto-immunity (234–237) (Figure 2). However, some “leakiness” in this process allows TAA-specific T cells possessing TCRs with low affinity to escape deletion (234, 236, 237) and persist, although at low precursor frequencies (238) (Figure 2). Unfortunately, as compared to PAA-specific T cells, which bear high-affinity TCRs (Figure 2), TAA-specific T cells exhibit limited effector and memory functions (234, 239). Coupled with the tendency of progressing tumors to generate a highly immunosuppressive microenvironment, this renders the insurgence of lifelong protective immunity nearly impossible (234). Of note, central and peripheral tolerance may not affect T cells reactive toward neo-tumor-specific antigens (neo-TSAs) e.g., tumor-specific neo-antigens that are generated de novo in the course of tumor progression because of mutational events (240, 241). However, the extent to which such neo-TSAs can elicit consistent “immunodominant” T cell reactivity is still a matter of investigation (240, 241). Nevertheless, in this context, inefficient T-cell stimulation can be overcome through the ICD-based improvement of effector T-cell functions (102). ICD can be further combined with checkpoint-blocking therapies, which potently reverse immunosuppression (209, 242). However, the lifelong maintenance of anti-tumor T cells remains a particularly hard challenge.

Figure 2

In the clinical reality, anticancer agents are administered to patients in a limited number of cycles. Even if these therapeutic regimens may attain optimal efficacy in terms of ICD induction, they are unlikely to ensure the lifelong persistence of TAA-directed T cells with low-affinity TCR (234, 243). This probably reflects the contraction of TAA-targeting T cells occurring once the immunostimulatory stimulus provided by ICD ceases, owing to peripheral tolerance mechanisms (234). Clinically, it may not be feasible to administer ICD inducers repeatedly over time, since many of them can cause lymphopenia (which negatively affects disease outcome), or are associated with other side effects (244). It has been proposed that active immunization with ICD-based anticancer vaccines (which are associated with robust immunogenicity) given in a repetitive manner may achieve this goal (Figure 2) (234, 243, 245). Thus, it will be important to test whether the long-term administration of ICD-based anticancer vaccines can sustain the effector function of TAA-specific T cells bearing low-affinity TCRs, hence, ensuring lifelong disease-free survival. Of note, in the case of hematological malignancies, this issue could be overcome upon the adoptive transfer of CTLs expressing chimeric antigen receptors (CARs) (1). However, whether CAR-expressing CTLs generate protective immunological memory in the absence of considerable side effects remains to be determined. Moreover, the use of this therapeutic strategy against solid malignancies is relatively challenging owing to lack of well-defined “unique” TAAs (1, 246).

Conclusion

The model of ICD has been considerably refined since the initial identification of a cell death modality manifesting apoptotic features but able to induce an adaptive immune response. This model strives to integrate several phenomena observed throughout the second half of the twentieth century in one therapeutically relevant platform. However, as discussed above, several challenges still need to be addressed. First, comprehensive testing should be performed in advanced experimental settings like GEMMs or orthotopic tumor models. Second, ICD resistance mechanisms should be characterized with precision. Third, various issues linked to the successful translation of ICD to cancer therapy will have to be resolved, including (but not limited to) treatment schedules, dosages, and combinatorial strategies. This translational drive also needs to be coupled with effective strategies for the discovery of new and effective ICD inducers. Drug screening programs are often complicated by the possibility of false-positive (due to bystander presence of DAMPs) (30) or false-negative (due to limited number of biomarkers used for screening) hits. This issue can only be ironed out by discovering new and common regulators of ICD, and integrating them into existing screening platforms. Last, but not least, it will be important to identify new ICD-related/derived biomarkers that can be used to improve current protocols of patient stratification and clinical decision making. We are positive that all these objectives are at reach.

References

• 1

  GalluzziLVacchelliEBravo-San PedroJMBuqueASenovillaLBaraccoEEet alClassification of current anticancer immunotherapies. Oncotarget (2014) 5(24):12472–508.10.18632/oncotarget.2998

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 2

  KeppOTesniereAZitvogelLKroemerG. The immunogenicity of tumor cell death. Curr Opin Oncol (2009) 21(1):71–6.10.1097/CCO.0b013e32831bc375

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 3

  GargADDudekAMAgostinisP. Cancer immunogenicity, danger signals, and DAMPs: what, when, and how?Biofactors (2013) 39(4):355–67.10.1002/biof.1125

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 4

  BlankensteinTCouliePGGilboaEJaffeeEM. The determinants of tumour immunogenicity. Nat Rev Cancer (2012) 12(4):307–13.10.1038/nrc3246

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 5

  GargADNowisDGolabJVandenabeelePKryskoDVAgostinisP. Immunogenic cell death, DAMPs and anticancer therapeutics: an emerging amalgamation. Biochim Biophys Acta (2010) 1805(1):53–71.10.1016/j.bbcan.2009.08.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 6

  AnguilleSSmitsELLionEvan TendelooVFBernemanZN. Clinical use of dendritic cells for cancer therapy. Lancet Oncol (2014) 15(7):e257–67.10.1016/S1470-2045(13)70585-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 7

  ChiangCLKandalaftLECoukosG. Adjuvants for enhancing the immunogenicity of whole tumor cell vaccines. Int Rev Immunol (2011) 30(2–3):150–82.10.3109/08830185.2011.572210

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 8

  ParishCR. Cancer immunotherapy: the past, the present and the future. Immunol Cell Biol (2003) 81(2):106–13.10.1046/j.0818-9641.2003.01151.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 9

  ColeyWB. The treatment of malignant tumors by repeated inoculations of erysipelas: with a report of ten original cases. Am J Med Sci (1893) 105:487–511.10.1097/00000441-189305000-00001

  • CrossRef
  • Google Scholar
  • View reference in article

• 10

  TsungKNortonJA. Lessons from Coley’s toxin. Surg Oncol (2006) 15(1):25–8.10.1016/j.suronc.2006.05.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 11

  CouliePGVan den EyndeBJvan der BruggenPBoonT. Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nat Rev Cancer (2014) 14(2):135–46.10.1038/nrc3670

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 12

  LiaoSKCarrDH. Comparative immunogenicity of irradiated, neuraminidase treated, and fused cells of a strain-restricted sarcoma. Z Krebsforsch klin Onkol Cancer Res Clin Oncol (1974) 82(2):133–42.

  • Google Scholar
  • View reference in article

• 13

  MilasLWithersHR. Nonspecific immunotherapy of malignant tumors. Radiology (1976) 118(1):211–8.10.1148/118.1.211

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 14

  BogdenAEEsberHJ. Influence of surgery, irradiation, chemotherapy, and immunotherapy on growth of a metastasizing rat mammary adenocarcinoma. Natl Cancer Inst Monogr (1978) (49):97–100.

  • Pubmed Abstract
  • Google Scholar
  • View reference in article

• 15

  DicksonJAShahSA. Hyperthermia: the immune response and tumor metastasis. Natl Cancer Inst Monogr (1982) 61:183–92.

  • Pubmed Abstract
  • Google Scholar
  • View reference in article

• 16

  SuitHDWalkerAM. Assessment of the response of tumours to radiation: clinical and experimental studies. Br J Cancer Suppl (1980) 4:1–10.

  • Pubmed Abstract
  • Google Scholar
  • View reference in article

• 17

  RichertLOrAShinitzkyM. Promotion of tumor antigenicity in EL-4 leukemia cells by hydrostatic pressure. Cancer Immunol Immunother (1986) 22(2):119–24.10.1007/BF00199125

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 18

  GalluzziLSenovillaLZitvogelLKroemerG. The secret ally: immunostimulation by anticancer drugs. Nat Rev Drug Discov (2012) 11(3):215–33.10.1038/nrd3626

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 19

  GreenDRFergusonTZitvogelLKroemerG. Immunogenic and tolerogenic cell death. Nat Rev Immunol (2009) 9(5):353–63.10.1038/nri2545

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 20

  MatzingerP. Tolerance, danger, and the extended family. Annu Rev Immunol (1994) 12:991–1045.10.1146/annurev.iy.12.040194.005015

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 21

  MatzingerP. The danger model: a renewed sense of self. Science (2002) 296(5566):301–5.10.1126/science.1071059

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 22

  LandWSchneebergerHSchleibnerSIllnerWDAbendrothDRutiliGet alThe beneficial effect of human recombinant superoxide dismutase on acute and chronic rejection events in recipients of cadaveric renal transplants. Transplantation (1994) 57(2):211–7.10.1097/00007890-199401001-00010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 23

  SeongSYMatzingerP. Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses. Nat Rev Immunol (2004) 4(6):469–78.10.1038/nri1372

  • CrossRef
  • Google Scholar
  • View reference in article

• 24

  RubartelliALotzeMT. Inside, outside, upside down: damage-associated molecular-pattern molecules (DAMPs) and redox. Trends Immunol (2007) 28(10):429–36.10.1016/j.it.2007.08.004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 25

  LiGTangDLotzeMT. Menage a trois in stress: DAMPs, redox and autophagy. Semin Cancer Biol (2013) 23(5):380–90.10.1016/j.semcancer.2013.08.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 26

  GargADMartinSGolabJAgostinisP. Danger signalling during cancer cell death: origins, plasticity and regulation. Cell Death Differ (2014) 21(1):26–38.10.1038/cdd.2013.48

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 27

  BianchiME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol (2007) 81(1):1–5.10.1189/jlb.0306164

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 28

  BondanzaAZimmermannVSRovere-QueriniPTurnayJDumitriuIEStachCMet alInhibition of phosphatidylserine recognition heightens the immunogenicity of irradiated lymphoma cells in vivo. J Exp Med (2004) 200(9):1157–65.10.1084/jem.20040327

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 29

  StachCMTurnayXVollREKernPMKolowosWBeyerTDet alTreatment with annexin V increases immunogenicity of apoptotic human T-cells in Balb/c mice. Cell Death Differ (2000) 7(10):911–5.10.1038/sj.cdd.4400715

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 30

  Dudek-PericAMFerreiraGBMuchowiczAWoutersJPradaNMartinSet alAntitumor immunity triggered by melphalan is potentiated by melanoma cell surface-associated calreticulin. Cancer Res (2015) 75(8):1603–14.10.1158/0008-5472.CAN-14-2089

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 31

  RondasDCrevecoeurID’HertogWFerreiraGBStaesAGargADet alCitrullinated glucose-regulated protein 78 is an autoantigen in type 1 diabetes. Diabetes (2015) 64(2):573–86.10.2337/db14-0621

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 32

  VenereauECasalgrandiMSchiraldiMAntoineDJCattaneoADe MarchisFet alMutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release. J Exp Med (2012) 209(9):1519–28.10.1084/jem.20120189

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 33

  WeydHAbeler-DornerLLinkeBMahrAJahndelVPfrangSet alAnnexin A1 on the surface of early apoptotic cells suppresses CD8+ T cell immunity. PLoS One (2013) 8(4):e62449.10.1371/journal.pone.0062449

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 34

  GargADDudekAMFerreiraGBVerfaillieTVandenabeelePKryskoDVet alROS-induced autophagy in cancer cells assists in evasion from determinants of immunogenic cell death. Autophagy (2013) 9(9):1292–307.10.4161/auto.25399

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 35

  GargADKryskoDVVerfaillieTKaczmarekAFerreiraGBMarysaelTet alA novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death. EMBO J (2012) 31(5):1062–79.10.1038/emboj.2011.497

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 36

  GhiringhelliFApetohLTesniereAAymericLMaYOrtizCet alActivation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nat Med (2009) 15(10):1170–8.10.1038/nm.2028

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 37

  ElliottMRChekeniFBTrampontPCLazarowskiERKadlAWalkSFet alNucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature (2009) 461(7261):282–6.10.1038/nature08296

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 38

  IwataAMorgan-StevensonVSchwartzBLiuLTupperJZhuXet alExtracellular BCL2 proteins are danger-associated molecular patterns that reduce tissue damage in murine models of ischemia-reperfusion injury. PLoS One (2010) 5(2):e9103.10.1371/journal.pone.0009103

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 39

  BabelovaAMorethKTsalastra-GreulWZeng-BrouwersJEickelbergOYoungMFet alBiglycan, a danger signal that activates the NLRP3 inflammasome via toll-like and P2X receptors. J Biol Chem (2009) 284(36):24035–48.10.1074/jbc.M109.014266

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 40

  SchaeferL. Extracellular matrix molecules: endogenous danger signals as new drug targets in kidney diseases. Curr Opin Pharmacol (2010) 10(2):185–90.10.1016/j.coph.2009.11.007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 41

  ObeidMTesniereAGhiringhelliFFimiaGMApetohLPerfettiniJLet alCalreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med (2007) 13(1):54–61.10.1038/nm1523

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 42

  GargADElsenSKryskoDVVandenabeelePde WittePAgostinisP. Resistance to anticancer vaccination effect is controlled by a cancer cell-autonomous phenotype that disrupts immunogenic phagocytic removal. Oncotarget (2015) 6(29):26841–60.10.18632/oncotarget.4754

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 43

  KoksCAGargADEhrhardtMRivaMVandenberkLBoonLet alNewcastle disease virotherapy induces long-term survival and tumor-specific immune memory in orthotopic glioma through the induction of immunogenic cell death. Int J Cancer (2015) 136(5):E313–25.10.1002/ijc.29202

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 44

  GardaiSJMcPhillipsKAFraschSCJanssenWJStarefeldtAMurphy-UllrichJEet alCell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell (2005) 123(2):321–34.10.1016/j.cell.2005.08.032

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 45

  Garcia FernandezMTroianoLMorettiLNasiMPintiMSalvioliSet alEarly changes in intramitochondrial cardiolipin distribution during apoptosis. Cell Growth Differ (2002) 13(9):449–55.

  • Pubmed Abstract
  • Google Scholar

• 46

  SoriceMCircellaACristeaIMGarofaloTDi RenzoLAlessandriCet alCardiolipin and its metabolites move from mitochondria to other cellular membranes during death receptor-mediated apoptosis. Cell Death Differ (2004) 11(10):1133–45.10.1038/sj.cdd.4401457

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 47

  KorbelikMBanathJSunJCanalsDHannunYASeparovicD. Ceramide and sphingosine-1-phosphate act as photodynamic therapy-elicited damage-associated molecular patterns: cell surface exposure. Int Immunopharmacol (2014) 20(2):359–65.10.1016/j.intimp.2014.03.016

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 48

  HorinoKNishiuraHOhsakoTShibuyaYHiraokaTKitamuraNet alA monocyte chemotactic factor, S19 ribosomal protein dimer, in phagocytic clearance of apoptotic cells. Lab Invest (1998) 78(5):603–17.

  • Pubmed Abstract
  • Google Scholar

• 49

  NishimuraTHorinoKNishiuraHShibuyaYHiraokaTTanaseSet alApoptotic cells of an epithelial cell line, AsPC-1, release monocyte chemotactic S19 ribosomal protein dimer. J Biochem (2001) 129(3):445–54.10.1093/oxfordjournals.jbchem.a002876

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 50

  PeterCWesselborgSLauberK. Role of attraction and danger signals in the uptake of apoptotic and necrotic cells and its immunological outcome. In: KryskoDVVandenabeeleP, editors. Phagocytosis of Dying Cells. Berlin: Springer Science + Business Media B.V. (2009). p. 63–101.

  • Google Scholar

• 51

  YamamotoT. Roles of the ribosomal protein S19 dimer and the C5a receptor in pathophysiological functions of phagocytic leukocytes. Pathol Int (2007) 57(1):1–11.10.1111/j.1440-1827.2007.02049.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 52

  StruckJUhleinMMorgenthalerNGFurstWHoflichCBahramiSet alRelease of the mitochondrial enzyme carbamoyl phosphate synthase under septic conditions. Shock (2005) 23(6):533–8.

  • Pubmed Abstract
  • Google Scholar

• 53

  KryskoDVGargADKaczmarekAKryskoOAgostinisPVandenabeeleP. Immunogenic cell death and DAMPs in cancer therapy. Nat Rev Cancer (2012) 12(12):860–75.10.1038/nrc3380

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 54

  PulleritsRBokarewaMJonssonIMVerdrenghMTarkowskiA. Extracellular cytochrome c, a mitochondrial apoptosis-related protein, induces arthritis. Rheumatology (Oxford) (2005) 44(1):32–9.10.1093/rheumatology/keh406

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 55

  CodinaRVanasseAKelekarAVezysVJemmersonR. Cytochrome c-induced lymphocyte death from the outside in: inhibition by serum leucine-rich alpha-2-glycoprotein-1. Apoptosis (2010) 15(2):139–52.10.1007/s10495-009-0412-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 56

  YoonKWByunSKwonEHwangSYChuKHirakiMet alControl of signaling-mediated clearance of apoptotic cells by the tumor suppressor p53. Science (2015) 349(6247):1261669.10.1126/science.1261669

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 57

  KaoJHouckKFanYHaehnelILibuttiSKKaytonMLet alCharacterization of a novel tumor-derived cytokine. Endothelial-monocyte activating polypeptide II. J Biol Chem (1994) 269(40):25106–19.

  • Pubmed Abstract
  • Google Scholar

• 58

  KniesUEBehrensdorfHAMitchellCADeutschURisauWDrexlerHCet alRegulation of endothelial monocyte-activating polypeptide II release by apoptosis. Proc Natl Acad Sci U S A (1998) 95(21):12322–7.10.1073/pnas.95.21.12322

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 59

  AhrensSZelenaySSanchoDHancPKjaerSFeestCet alF-actin is an evolutionarily conserved damage-associated molecular pattern recognized by DNGR-1, a receptor for dead cells. Immunity (2012) 36(4):635–45.10.1016/j.immuni.2012.03.008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 60

  ChibaSBaghdadiMAkibaHYoshiyamaHKinoshitaIDosaka-AkitaHet alTumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. Nat Immunol (2012) 13(9):832–42.10.1038/ni.2376

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 61

  ZitvogelLKeppOKroemerG. Decoding cell death signals in inflammation and immunity. Cell (2010) 140(6):798–804.10.1016/j.cell.2010.02.015

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 62

  PletjushkinaOYFetisovaEKLyamzaevKGIvanovaOYDomninaLVVyssokikhMYet alLong-distance apoptotic killing of cells is mediated by hydrogen peroxide in a mitochondrial ROS-dependent fashion. Cell Death Differ (2005) 12(11):1442–4.10.1038/sj.cdd.4401685

  • CrossRef
  • Google Scholar

• 63

  GargADNowisDGolabJAgostinisP. Photodynamic therapy: illuminating the road from cell death towards anti-tumour immunity. Apoptosis (2010) 15(9):1050–71.10.1007/s10495-010-0479-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 64

  SuzukiSKulkarniAB. Extracellular heat shock protein HSP90beta secreted by MG63 osteosarcoma cells inhibits activation of latent TGF-beta1. Biochem Biophys Res Commun (2010) 398(3):525–31.10.1016/j.bbrc.2010.06.112

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 65

  KorbelikMSunJCecicI. Photodynamic therapy-induced cell surface expression and release of heat shock proteins: relevance for tumor response. Cancer Res (2005) 65(3):1018–26.

  • Pubmed Abstract
  • Google Scholar

• 66

  CironeMDi RenzoLLottiLVConteVTrivediPSantarelliRet alPrimary effusion lymphoma cell death induced by bortezomib and AG 490 activates dendritic cells through CD91. PLoS One (2012) 7(3):e31732.10.1371/journal.pone.0031732

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 67

  ZuninoBRubio-PatinoCVillaEMeynetOProicsECornilleAet alHyperthermic intraperitoneal chemotherapy leads to an anticancer immune response via exposure of cell surface heat shock protein 90. Oncogene (2015).10.1038/onc.2015.82

  • CrossRef
  • Google Scholar

• 68

  ZhouZYamamotoYSugaiFYoshidaKKishimaYSumiHet alHepatoma-derived growth factor is a neurotrophic factor harbored in the nucleus. J Biol Chem (2004) 279(26):27320–6.10.1074/jbc.M308650200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 69

  HuangHEvankovichJYanWNaceGZhangLRossMet alEndogenous histones function as alarmins in sterile inflammatory liver injury through toll-like receptor 9 in mice. Hepatology (2011) 54(3):999–1008.10.1002/hep.24501

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 70

  ApetohLGhiringhelliFTesniereAObeidMOrtizCCriolloAet alToll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med (2007) 13(9):1050–9.10.1038/nm1622

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 71

  SeminoCAngeliniGPoggiARubartelliA. NK/iDC interaction results in IL-18 secretion by DCs at the synaptic cleft followed by NK cell activation and release of the DC maturation factor HMGB1. Blood (2005) 106(2):609–16.10.1182/blood-2004-10-3906

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 72

  ScaffidiPMisteliTBianchiME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature (2002) 418(6894):191–5.10.1038/nature00858

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 73

  ThorburnJHoritaHRedzicJHansenKFrankelAEThorburnA. Autophagy regulates selective HMGB1 release in tumor cells that are destined to die. Cell Death Differ (2009) 16(1):175–83.10.1038/cdd.2008.143

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 74

  YangDPostnikovYVLiYTewaryPde la RosaGWeiF. High-mobility group nucleosome-binding protein 1 acts as an alarmin and is critical for lipopolysaccharide-induced immune responses. J Exp Med (2012) 209(1):157–71.10.1084/jem.20101354

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 75

  CohenIRiderPCarmiYBraimanADotanSWhiteMRet alDifferential release of chromatin-bound IL-1alpha discriminates between necrotic and apoptotic cell death by the ability to induce sterile inflammation. Proc Natl Acad Sci U S A (2010) 107(6):2574–9.10.1073/pnas.0915018107

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 76

  Vanden BergheTKalaiMDeneckerGMeeusASaelensXVandenabeeleP. Necrosis is associated with IL-6 production but apoptosis is not. Cell Signal (2006) 18(3):328–35.10.1016/j.cellsig.2005.05.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 77

  LauberKBohnEKroberSMXiaoYJBlumenthalSGLindemannRKet alApoptotic cells induce migration of phagocytes via caspase-3-mediated release of a lipid attraction signal. Cell (2003) 113:717–30.10.1016/S0092-8674(03)00422-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 78

  ZhangQRaoofMChenYSumiYSursalTJungerWet alCirculating mitochondrial DAMPs cause inflammatory responses to injury. Nature (2010) 464(7285):104–7.10.1038/nature08780

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 79

  CollinsLVHajizadehSHolmeEJonssonIMTarkowskiA. Endogenously oxidized mitochondrial DNA induces in vivo and in vitro inflammatory responses. J Leukoc Biol (2004) 75(6):995–1000.10.1189/jlb.0703328

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 80

  GalluzziLKeppOKroemerG. Mitochondria: master regulators of danger signalling. Nat Rev Mol Cell Biol (2012) 13(12):780–8.10.1038/nrm3479

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 81

  ShiYEvansJERockKL. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature (2003) 425(6957):516–21.10.1038/nature01991

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 82

  CarpH. Mitochondrial N-formylmethionyl proteins as chemoattractants for neutrophils. J Exp Med (1982) 155(1):264–75.10.1084/jem.155.1.264

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 83

  RabietMJHuetEBoulayF. The N-formyl peptide receptors and the anaphylatoxin C5a receptors: an overview. Biochimie (2007) 89(9):1089–106.10.1016/j.biochi.2007.02.015

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 84

  CzapigaMGaoJLKirkALekstrom-HimesJ. Human platelets exhibit chemotaxis using functional N-formyl peptide receptors. Exp Hematol (2005) 33(1):73–84.10.1016/j.exphem.2004.09.010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 85

  MoghaddamAEGartlanKHKongLSattentauQJ. Reactive carbonyls are a major Th2-inducing damage-associated molecular pattern generated by oxidative stress. J Immunol (2011) 187(4):1626–33.10.4049/jimmunol.1003906

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 86

  MillerYIChoiSHWiesnerPFangLHarkewiczRHartvigsenKet alOxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity. Circ Res (2011) 108(2):235–48.10.1161/CIRCRESAHA.110.223875

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 87

  VandenberkLGargADVerschuereTKoksCBelmansJBeullensMet alIrradiation of necrotic cancer cells employed for pulsing dendritic cells (DCs), potentiates DC vaccine-induced antitumor immunity against high-grade glioma. Oncoimmunology (2015).10.1080/2162402X.2015.1083669

  • CrossRef
  • Google Scholar

• 88

  RiddellJRWangXYMindermanHGollnickSO. Peroxiredoxin 1 stimulates secretion of proinflammatory cytokines by binding to TLR4. J Immunol (2010) 184(2):1022–30.10.4049/jimmunol.0901945

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 89

  FranzSHerrmannKFurnrohrBGSheriffAFreyBGaiplUSet alAfter shrinkage apoptotic cells expose internal membrane-derived epitopes on their plasma membranes. Cell Death Differ (2007) 14(4):733–42.10.1038/sj.cdd.4402066

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 90

  PetrovskiGZahuczkyGKatonaKVerebGMartinetWNemesZet alClearance of dying autophagic cells of different origin by professional and non-professional phagocytes. Cell Death Differ (2007) 14(6):1117–28.10.1038/sj.cdd.4402112

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 91

  BrattonDLFadokVARichterDAKaileyJMGuthrieLAHensonPM. Appearance of phosphatidylserine on apoptotic cells requires calcium-mediated nonspecific flip-flop and is enhanced by loss of the aminophospholipid translocase. J Biol Chem (1997) 272(42):26159–65.10.1074/jbc.272.42.26159

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 92

  MartinSJReutelingspergerCPMcGahonAJRaderJAvan SchieRCLaFaceDMet alEarly redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of Bcl-2 and Abl. J Exp Med (1995) 182(5):1545–56.10.1084/jem.182.5.1545

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 93

  BrouckaertGKalaiMKryskoDVSaelensXVercammenDNdlovuMNet alPhagocytosis of necrotic cells by macrophages is phosphatidylserine dependent and does not induce inflammatory cytokine production. Mol Biol Cell (2004) 15(3):1089–100.10.1091/mbc.E03-09-0668

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 94

  DonatoR. RAGE: a single receptor for several ligands and different cellular responses: the case of certain S100 proteins. Curr Mol Med (2007) 7(8):711–24.10.2174/156652407783220688

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 95

  GohFGPiccininiAMKrausgruberTUdalovaIAMidwoodKS. Transcriptional regulation of the endogenous danger signal tenascin-C: a novel autocrine loop in inflammation. J Immunol (2010) 184(5):2655–62.10.4049/jimmunol.0903359

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 96

  KrispinABlediYAtallahMTrahtembergUVerbovetskiINahariEet alApoptotic cell thrombospondin-1 and heparin-binding domain lead to dendritic-cell phagocytic and tolerizing states. Blood (2006) 108(10):3580–9.10.1182/blood-2006-03-013334

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 97

  GalluzziLBravo-San PedroJMVitaleIAaronsonSAAbramsJMAdamDet alEssential versus accessory aspects of cell death: recommendations of the NCCD 2015. Cell Death Differ (2015) 22(1):58–73.10.1038/cdd.2014.137

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 98

  MelcherATodrykSHardwickNFordMJacobsonMVileRG. Tumor immunogenicity is determined by the mechanism of cell death via induction of heat shock protein expression. Nat Med (1998) 4(5):581–7.10.1038/nm0598-581

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 99

  GoughMJMelcherAACrittendenMRSanchez-PerezLVoellmyRVileRG. Induction of cell stress through gene transfer of an engineered heat shock transcription factor enhances tumor immunogenicity. Gene Ther (2004) 11(13):1099–104.10.1038/sj.gt.3302274

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 100

  SpisekRCharalambousAMazumderAVesoleDHJagannathSDhodapkarMV. Bortezomib enhances dendritic cell (DC)-mediated induction of immunity to human myeloma via exposure of cell surface heat shock protein 90 on dying tumor cells: therapeutic implications. Blood (2007) 109(11):4839–45.10.1182/blood-2006-10-054221

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 101

  CasaresNPequignotMOTesniereAGhiringhelliFRouxSChaputNet alCaspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J Exp Med (2005) 202(12):1691–701.10.1084/jem.20050915

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 102

  KroemerGGalluzziLKeppOZitvogelL. Immunogenic cell death in cancer therapy. Annu Rev Immunol (2013) 31:51–72.10.1146/annurev-immunol-032712-100008

  • CrossRef
  • Google Scholar

• 103

  GargADDudek-PericAMRomanoEAgostinisP. Immunogenic cell death. Int J Dev Biol (2015) 59:131–40.10.1387/ijdb.150061pa

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 104

  KeppOSenovillaLVitaleIVacchelliEAdjemianSAgostinisPet alConsensus guidelines for the detection of immunogenic cell death. Oncoimmunology (2014) 3(9):e955691.10.4161/21624011.2014.955691

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 105

  DudekAMMartinSGargADAgostinisP. Immature, semi-mature, and fully mature dendritic cells: toward a DC-cancer cells interface that augments anticancer immunity. Front Immunol (2014) 4:438.10.3389/fimmu.2013.00438

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 106

  MaYAdjemianSMattarolloSRYamazakiTAymericLYangHet alAnticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells. Immunity (2013) 38(4):729–41.10.1016/j.immuni.2013.03.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 107

  ZhangJGCzabotarPEPolicheniANCaminschiIWanSSKitsoulisSet alThe dendritic cell receptor Clec9A binds damaged cells via exposed actin filaments. Immunity (2012) 36(4):646–57.10.1016/j.immuni.2012.03.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 108

  GarnettCTPalenaCChakrabortyMTsangKYSchlomJHodgeJW. Sublethal irradiation of human tumor cells modulates phenotype resulting in enhanced killing by cytotoxic T lymphocytes. Cancer Res (2004) 64(21):7985–94.10.1158/0008-5472.CAN-04-1525

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 109

  HodgeJWGarnettCTFarsaciBPalenaCTsangKYFerroneSet alChemotherapy-induced immunogenic modulation of tumor cells enhances killing by cytotoxic T lymphocytes and is distinct from immunogenic cell death. Int J Cancer (2013) 133(3):624–36.10.1002/ijc.28070

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 110

  GameiroSRJammehMLWattenbergMMTsangKYFerroneSHodgeJW. Radiation-induced immunogenic modulation of tumor enhances antigen processing and calreticulin exposure, resulting in enhanced T-cell killing. Oncotarget (2014) 5(2):403–16.10.18632/oncotarget.1719

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 111

  MichaudMMartinsISukkurwalaAQAdjemianSMaYPellegattiPet alAutophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science (2011) 334(6062):1573–7.10.1126/science.1208347

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 112

  GargADDudekAMAgostinisP. Calreticulin surface exposure is abrogated in cells lacking, chaperone-mediated autophagy-essential gene, LAMP2A. Cell Death Dis (2013) 4:e826.10.1038/cddis.2013.372

  • CrossRef
  • Google Scholar

• 113

  MartinsIWangYMichaudMMaYSukkurwalaAQShenSet alMolecular mechanisms of ATP secretion during immunogenic cell death. Cell Death Differ (2014) 21(1):79–91.10.1038/cdd.2013.75

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 114

  KazamaHRicciJEHerndonJMHoppeGGreenDRFergusonTA. Induction of immunological tolerance by apoptotic cells requires caspase-dependent oxidation of high-mobility group box-1 protein. Immunity (2008) 29(1):21–32.10.1016/j.immuni.2008.05.013

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 115

  JubeSRiveraZBianchiMEPowersAWangEPaganoISet alCancer cell secretion of the DAMP protein HMGB1 supports progression in malignant mesothelioma. Cancer Res (2012) 72(13):3290–301.10.1158/0008-5472.CAN-11-3481

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 116

  GargADKryskoDVVandenabeelePAgostinisP. Hypericin-based photodynamic therapy induces surface exposure of damage-associated molecular patterns like HSP70 and calreticulin. Cancer Immunol Immunother (2012) 61(2):215–21.10.1007/s00262-011-1184-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 117

  LancasterGIFebbraioMA. Exosome-dependent trafficking of HSP70: a novel secretory pathway for cellular stress proteins. J Biol Chem (2005) 280(24):23349–55.10.1074/jbc.M502017200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 118

  MambulaSSCalderwoodSK. Heat shock protein 70 is secreted from tumor cells by a nonclassical pathway involving lysosomal endosomes. J Immunol (2006) 177(11):7849–57.10.4049/jimmunol.177.11.7849

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 119

  VegaVLRodriguez-SilvaMFreyTGehrmannMDiazJCSteinemCet alHsp70 translocates into the plasma membrane after stress and is released into the extracellular environment in a membrane-associated form that activates macrophages. J Immunol (2008) 180(6):4299–307.10.4049/jimmunol.180.6.4299

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 120

  KotterBFreyBWinderlMRubnerYScheithauerHSieberRet alThe in vitro immunogenic potential of caspase-3 proficient breast cancer cells with basal low immunogenicity is increased by hypofractionated irradiation. Radiat Oncol (2015) 10(1):197.10.1186/s13014-015-0506-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 121

  MulthoffGBotzlerCWiesnetMMullerEMeierTWilmannsWet alA stress-inducible 72-kDa heat-shock protein (HSP72) is expressed on the surface of human tumor cells, but not on normal cells. Int J Cancer (1995) 61(2):272–9.10.1002/ijc.2910610222

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 122

  GastparRGehrmannMBauseroMAAseaAGrossCSchroederJAet alHeat shock protein 70 surface-positive tumor exosomes stimulate migratory and cytolytic activity of natural killer cells. Cancer Res (2005) 65(12):5238–47.10.1158/0008-5472.CAN-04-3804

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 123

  PanaretakisTKeppOBrockmeierUTesniereABjorklundACChapmanDCet alMechanisms of pre-apoptotic calreticulin exposure in immunogenic cell death. EMBO J (2009) 28(5):578–90.10.1038/emboj.2009.1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 124

  MadeoFDurchschlagMKeppOPanaretakisTZitvogelLFrohlichKUet alPhylogenetic conservation of the preapoptotic calreticulin exposure pathway from yeast to mammals. Cell Cycle (2009) 8(4):639–42.10.4161/cc.8.4.7794

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 125

  MartinSDudek-PericAMMaesHGargADGabrysiakMDemirsoySet alConcurrent MEK and autophagy inhibition is required to restore cell death associated danger-signalling in vemurafenib-resistant melanoma cells. Biochem Pharmacol (2015) 93(3):290–304.10.1016/j.bcp.2014.12.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 126

  SzklarczykDFranceschiniAWyderSForslundKHellerDHuerta-CepasJet alSTRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res (2015) 43(Database issue):D447–52.10.1093/nar/gku1003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 127

  DudekAMGargADKryskoDVDe RuysscherDAgostinisP. Inducers of immunogenic cancer cell death. Cytokine Growth Factor Rev (2013) 24(4):319–33.10.1016/j.cytogfr.2013.01.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 128

  BezuLGomes-de-SilvaLCDewitteHBreckpotKFucikovaJSpisekRet alCombinatorial strategies for the induction of immunogenic cell death. Front Immunol (2015) 6:187.10.3389/fimmu.2015.00187

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 129

  SiuralaMBramanteSVassilevLHirvinenMParviainenSTahtinenSet alOncolytic adenovirus and doxorubicin-based chemotherapy results in synergistic antitumor activity against soft-tissue sarcoma. Int J Cancer (2015) 136(4):945–54.10.1002/ijc.29048

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 130

  MengerLVacchelliEAdjemianSMartinsIMaYShenSet alCardiac glycosides exert anticancer effects by inducing immunogenic cell death. Sci Transl Med (2012) 4(143):143ra99.10.1126/scitranslmed.3003807

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 131

  PanaretakisTJozaNModjtahediNTesniereAVitaleIDurchschlagMet alThe co-translocation of ERp57 and calreticulin determines the immunogenicity of cell death. Cell Death Differ (2008) 15(9):1499–509.10.1038/cdd.2008.67

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 132

  TufiRPanaretakisTBianchiKCriolloAFaziBDi SanoFet alReduction of endoplasmic reticulum Ca2+ levels favors plasma membrane surface exposure of calreticulin. Cell Death Differ (2008) 15(2):274–82.10.1038/sj.cdd.4402275

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 133

  MartinsIKeppOSchlemmerFAdjemianSTaillerMShenSet alRestoration of the immunogenicity of cisplatin-induced cancer cell death by endoplasmic reticulum stress. Oncogene (2011) 30(10):1147–58.10.1038/onc.2010.500

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 134

  VerfaillieTRubioNGargADBultynckGRizzutoRDecuypereJPet alPERK is required at the ER-mitochondrial contact sites to convey apoptosis after ROS-based ER stress. Cell Death Differ (2012) 19(11):1880–91.10.1038/cdd.2012.74

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 135

  GalluzziLBravo-San PedroJMKroemerG. Organelle-specific initiation of cell death. Nat Cell Biol (2014) 16(8):728–36.10.1038/ncb3005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 136

  ChaurioRAMunozLEMaueroderCJankoCHarrerTFurnrohrBGet alThe progression of cell death affects the rejection of allogeneic tumors in immune-competent mice – implications for cancer therapy. Front Immunol (2014) 5:560.10.3389/fimmu.2014.00560

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 137

  GargADMaesHvan VlietARAgostinisP. Targeting the hallmarks of cancer with therapy-induced endoplasmic reticulum (ER) stress. Mol Cell Oncol (2015) 2(1):e975089.10.4161/23723556.2014.975089

  • CrossRef
  • Google Scholar

• 138

  van VlietARMartinSGargADAgostinisP. The PERKs of damage-associated molecular patterns mediating cancer immunogenicity: from sensor to the plasma membrane and beyond. Semin Cancer Biol (2015) 33:74–85.10.1016/j.semcancer.2015.03.010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 139

  SukkurwalaAQAdjemianSSenovillaLMichaudMSpaggiariSVacchelliEet alScreening of novel immunogenic cell death inducers within the NCI mechanistic diversity set. Oncoimmunology (2014) 3:e28473.10.4161/onci.28473

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 140

  WongDYOngWWAngWH. Induction of immunogenic cell death by chemotherapeutic platinum complexes. Angew Chem Int Ed Engl (2015) 54(22):6483–7.10.1002/anie.201500934

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 141

  SistiguAYamazakiTVacchelliEChabaKEnotDPAdamJet alCancer cell-autonomous contribution of type I interferon signaling to the efficacy of chemotherapy. Nat Med (2014) 20(11):1301–9.10.1038/nm.3708

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 142

  RamakrishnanRGabrilovichDI. The role of mannose-6-phosphate receptor and autophagy in influencing the outcome of combination therapy. Autophagy (2013) 9(4):615–6.10.4161/auto.23485

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 143

  KaminskiJMShinoharaESummersJBNiermannKJMorimotoABrousalJ. The controversial abscopal effect. Cancer Treat Rev (2005) 31(3):159–72.10.1016/j.ctrv.2005.03.004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 144

  GoldenEBFrancesDPellicciottaIDemariaSHelen Barcellos-HoffMFormentiSC. Radiation fosters dose-dependent and chemotherapy-induced immunogenic cell death. Oncoimmunology (2014) 3:e28518.10.4161/onci.28518

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 145

  GarridoGRabasaASanchezBLopezMVBlancoRLopezAet alInduction of immunogenic apoptosis by blockade of epidermal growth factor receptor activation with a specific antibody. J Immunol (2011) 187(10):4954–66.10.4049/jimmunol.1003477

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 146

  BugautHBruchardMBergerHDerangereVOdoulLEuvrardRet alBleomycin exerts ambivalent antitumor immune effect by triggering both immunogenic cell death and proliferation of regulatory T cells. PLoS One (2013) 8(6):e65181.10.1371/journal.pone.0065181

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 147

  DiaconuICerulloVHirvinenMLEscutenaireSUgoliniMPesonenSKet alImmune response is an important aspect of the antitumor effect produced by a CD40L-encoding oncolytic adenovirus. Cancer Res (2012) 72(9):2327–38.10.1158/0008-5472.CAN-11-2975

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 148

  HemminkiOParviainenSJuhilaJTurkkiRLinderNLundinJet alImmunological data from cancer patients treated with Ad5/3-E2F-Delta24-GMCSF suggests utility for tumor immunotherapy. Oncotarget (2015) 6(6):4467–81.10.18632/oncotarget.2901

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 149

  SunCWangHMaoSLiuJLiSWangJ. Reactive oxygen species involved in CT26 immunogenic cell death induced by Clostridium difficile toxin B. Immunol Lett (2015) 164(2):65–71.10.1016/j.imlet.2015.02.007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 150

  MiyamotoSInoueHNakamuraTYamadaMSakamotoCUrataYet alCoxsackievirus B3 Is an oncolytic virus with immunostimulatory properties that is active against lung Adenocarcinoma. Cancer Res (2012) 72(10):2609–21.10.1158/0008-5472.CAN-11-3185

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 151

  VacchelliEEggermontASautes-FridmanCGalonJZitvogelLKroemerGet alTrial watch: oncolytic viruses for cancer therapy. Oncoimmunology (2013) 2(6):e24612.10.4161/onci.22789

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 152

  SchiavoniGSistiguAValentiniMMatteiFSestiliPSpadaroFet alCyclophosphamide synergizes with type I interferons through systemic dendritic cell reactivation and induction of immunogenic tumor apoptosis. Cancer Res (2011) 71(3):768–78.10.1158/0008-5472.CAN-10-2788

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 153

  ViaudSSaccheriFMignotGYamazakiTDaillereRHannaniDet alThe intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science (2013) 342(6161):971–6.10.1126/science.1240537

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 154

  FucikovaJMoserovaITruxovaIHermanovaIVancurovaIPartlovaSet alHigh hydrostatic pressure induces immunogenic cell death in human tumor cells. Int J Cancer (2014) 135(5):1165–77.10.1002/ijc.28766

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 155

  AdkinsIFucikovaJGargADAgostinisPSpisekR. Physical modalities inducing immunogenic tumor cell death for cancer immunotherapy. Oncoimmunology (2014) 3:e968434.10.4161/21624011.2014.968434

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 156

  WeissEMMeisterSJankoCEbelNSchluckerEMeyer-PittroffRet alHigh hydrostatic pressure treatment generates inactivated mammalian tumor cells with immunogeneic features. J Immunotoxicol (2010) 7(3):194–204.10.3109/15476911003657414

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 157

  GargADAgostinisP. ER stress, autophagy and immunogenic cell death in photodynamic therapy-induced anti-cancer immune responses. Photochem Photobiol Sci (2014) 13(3):474–87.10.1039/c3pp50333j

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 158

  YuZGengJZhangMZhouYFanQChenJ. Treatment of osteosarcoma with microwave thermal ablation to induce immunogenic cell death. Oncotarget (2014) 5(15):6526–39.10.18632/oncotarget.2310

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 159

  ZamarinDHolmgaardRBSubudhiSKParkJSMansourMPalesePet alLocalized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci Transl Med (2014) 6(226):226ra32.10.1126/scitranslmed.3008095

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 160

  ChenHMWangPHChenSSWenCCChenYHYangWCet alShikonin induces immunogenic cell death in tumor cells and enhances dendritic cell-based cancer vaccine. Cancer Immunol Immunother (2012) 61(11):1989–2002.10.1007/s00262-012-1258-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 161

  KorbelikMDoughertyGJ. Photodynamic therapy-mediated immune response against subcutaneous mouse tumors. Cancer Res (1999) 59(8):1941–6.

  • Pubmed Abstract
  • Google Scholar

• 162

  KroslGKorbelikMDoughertyGJ. Induction of immune cell infiltration into murine SCCVII tumour by photofrin-based photodynamic therapy. Br J Cancer (1995) 71(3):549–55.10.1038/bjc.1995.108

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 163

  KorbelikMStottBSunJ. Photodynamic therapy-generated vaccines: relevance of tumour cell death expression. Br J Cancer (2007) 97(10):1381–7.10.1038/sj.bjc.6604059

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 164

  KorbelikMZhangWMerchantS. Involvement of damage-associated molecular patterns in tumor response to photodynamic therapy: surface expression of calreticulin and high-mobility group box-1 release. Cancer Immunol Immunother (2011) 60(10):1431–7.10.1007/s00262-011-1047-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 165

  DuewellPStegerALohrHBourhisHHoelzHKirchleitnerSVet alRIG-I-like helicases induce immunogenic cell death of pancreatic cancer cells and sensitize tumors toward killing by CD8 T cells. Cell Death Differ (2014) 21(12):1825–37.10.1038/cdd.2014.96

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 166

  WestACMattarolloSRShorttJCluseLAChristiansenAJSmythMJet alAn intact immune system is required for the anticancer activities of histone deacetylase inhibitors. Cancer Res (2013) 73(24):7265–76.10.1158/0008-5472.CAN-13-0890

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 167

  YangYLiXJChenZZhuXXWangJZhangLBet alWogonin induced calreticulin/annexin A1 exposure dictates the immunogenicity of cancer cells in a PERK/AKT dependent manner. PLoS One (2012) 7(12):e50811.10.1371/journal.pone.0050811

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 168

  PanzariniEInguscioVFimiaGMDiniL. Rose Bengal acetate photodynamic therapy (RBAc-PDT) induces exposure and release of damage-associated molecular patterns (DAMPs) in human HeLa cells. PLoS One (2014) 9(8):e105778.10.1371/journal.pone.0105778

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 169

  MolinariRD’EliseoDManziLZollaLVelottiFMerendinoN. The n3-polyunsaturated fatty acid docosahexaenoic acid induces immunogenic cell death in human cancer cell lines via pre-apoptotic calreticulin exposure. Cancer Immunol Immunother (2011) 60(10):1503–7.10.1007/s00262-011-1074-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 170

  D’EliseoDManziLVelottiF. Capsaicin as an inducer of damage-associated molecular patterns (DAMPs) of immunogenic cell death (ICD) in human bladder cancer cells. Cell Stress Chaperones (2013) 18(6):801–8.10.1007/s12192-013-0422-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 171

  Gilardini MontaniMSD’EliseoDCironeMDi RenzoLFaggioniASantoniAet alCapsaicin-mediated apoptosis of human bladder cancer cells activates dendritic cells via CD91. Nutrition (2015) 31(4):578–81.10.1016/j.nut.2014.05.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 172

  JanewayC. Immunobiology: The Immune System in Health and Disease. 6th ed. New York, NY: Garland Science (2005). 823 p.

  • Google Scholar

• 173

  FucikovaJKralikovaPFialovaABrtnickyTRobLBartunkovaJet alHuman tumor cells killed by anthracyclines induce a tumor-specific immune response. Cancer Res (2011) 71(14):4821–33.10.1158/0008-5472.CAN-11-0950

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 174

  KryskoDVKaczmarekAKryskoOHeyndrickxLWoznickiJBogaertPet alTLR-2 and TLR-9 are sensors of apoptosis in a mouse model of doxorubicin-induced acute inflammation. Cell Death Differ (2011) 18(8):1316–25.10.1038/cdd.2011.4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 175

  TsengLMLiuCYChangKCChuPYShiauCWChenKF. CIP2A is a target of bortezomib in human triple negative breast cancer cells. Breast Cancer Res (2012) 14(2):R68.10.1186/bcr3175

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 176

  DaviesAMLaraPNJrMackPCGandaraDR. Incorporating bortezomib into the treatment of lung cancer. Clin Cancer Res (2007) 13(15 Pt 2):s4647–51.10.1158/1078-0432.CCR-07-0334

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 177

  HuangTLiSLiGTianYWangHShiLet alUtility of Clostridium difficile toxin B for inducing anti-tumor immunity. PLoS One (2014) 9(10):e110826.10.1371/journal.pone.0110826

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 178

  BravimFde FreitasJMFernandesAAFernandesPM. High hydrostatic pressure and the cell membrane: stress response of Saccharomyces cerevisiae. Ann N Y Acad Sci (2010) 1189:127–32.10.1111/j.1749-6632.2009.05182.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 179

  SenovillaLVitaleIMartinsITaillerMPailleretCMichaudMet alAn immunosurveillance mechanism controls cancer cell ploidy. Science (2012) 337(6102):1678–84.10.1126/science.1224922

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 180

  KorbelikM. Cancer vaccines generated by photodynamic therapy. Photochem Photobiol Sci (2011) 10(5):664–9.10.1039/c0pp00343c

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 181

  GargADKryskoDVVandenabeelePAgostinisP. DAMPs and PDT-mediated photo-oxidative stress: exploring the unknown. Photochem Photobiol Sci (2011) 10(5):670–80.10.1039/c0pp00294a

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 182

  ChenJXieJJiangZWangBWangYHuX. Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2. Oncogene (2011) 30(42):4297–306.10.1038/onc.2011.137

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 183

  TsaiCFYehWLHuangSMTanTWLuDY. Wogonin induces reactive oxygen species production and cell apoptosis in human glioma cancer cells. Int J Mol Sci (2012) 13(8):9877–92.10.3390/ijms13089877

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 184

  SanovicRVerwangerTHartlAKrammerB. Low dose hypericin-PDT induces complete tumor regression in BALB/c mice bearing CT26 colon carcinoma. Photodiagnosis Photodyn Ther (2011) 8(4):291–6.10.1016/j.pdpdt.2011.04.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 185

  GargADKryskoDVVandenabeelePAgostinisP. The emergence of phox-ER stress induced immunogenic apoptosis. OncoImmunology (2012) 1(5):787–9.10.4161/onci.19750

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 186

  LiuZZhangHMYuanJYeXTaylorGAYangD. The immunity-related GTPase Irgm3 relieves endoplasmic reticulum stress response during Coxsackievirus B3 infection via a PI3K/Akt dependent pathway. Cell Microbiol (2012) 14(1):133–46.10.1111/j.1462-5822.2011.01708.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 187

  BianJWangKKongXLiuHChenFHuMet alCaspase- and p38-MAPK-dependent induction of apoptosis in A549 lung cancer cells by Newcastle disease virus. Arch Virol (2011) 156(8):1335–44.10.1007/s00705-011-0987-y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 188

  GargADDe RuysscherDAgostinisP. Immunological metagene signatures derived from immunogenic cancer cell death associate with improved survival of patients with lung, breast or ovarian malignancies: a large-scale meta-analysis. Oncoimmunology (2015).10.1080/2162402X.2015.1069938

  • CrossRef
  • Google Scholar

• 189

  GalluzziLKeppOKroemerG. Enlightening the impact of immunogenic cell death in photodynamic cancer therapy. EMBO J (2012) 31(5):1055–7.10.1038/emboj.2012.2

  • CrossRef
  • Google Scholar

• 190

  GalluzziLPietrocolaFBravo-San PedroJMAmaravadiRKBaehreckeEHCecconiFet alAutophagy in malignant transformation and cancer progression. EMBO J (2015) 34(7):856–80.10.15252/embj.201490784

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 191

  MattarolloSRLoiSDuretHMaYZitvogelLSmythMJ. Pivotal role of innate and adaptive immunity in anthracycline chemotherapy of established tumors. Cancer Res (2011) 71(14):4809–20.10.1158/0008-5472.CAN-11-0753

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 192

  LinTJLinHTChangWTMitapalliSPHsiaoPWYinSYet alShikonin-enhanced cell immunogenicity of tumor vaccine is mediated by the differential effects of DAMP components. Mol Cancer (2015) 14:174.10.1186/s12943-015-0435-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 193

  MaYAymericLLocherCMattarolloSRDelahayeNFPereiraPet alContribution of IL-17-producing gamma delta T cells to the efficacy of anticancer chemotherapy. J Exp Med (2011) 208(3):491–503.10.1084/jem.20100269

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 194

  YangHYamazakiTPietrocolaFZhouHZitvogelLMaYet alSTAT3 inhibition enhances the therapeutic efficacy of immunogenic chemotherapy by stimulating type 1 interferon production by cancer cells. Cancer Res (2015) 75(18):3812–22.10.1158/0008-5472.CAN-15-1122

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 195

  CiampricottiMHauCSDoornebalCWJonkersJde VisserKE. Chemotherapy response of spontaneous mammary tumors is independent of the adaptive immune system. Nat Med (2012) 18(3):344–6.10.1038/nm.2652

  • CrossRef
  • Google Scholar

• 196

  GouldSEJunttilaMRde SauvageFJ. Translational value of mouse models in oncology drug development. Nat Med (2015) 21(5):431–9.10.1038/nm.3853

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 197

  TesniereASchlemmerFBoigeVKeppOMartinsIGhiringhelliFet alImmunogenic death of colon cancer cells treated with oxaliplatin. Oncogene (2010) 29(4):482–91.10.1038/onc.2009.356

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 198

  HannesdottirLTymoszukPParajuliNWasmerMHPhilippSDaschilNet alLapatinib and doxorubicin enhance the Stat1-dependent antitumor immune response. Eur J Immunol (2013) 43(10):2718–29.10.1002/eji.201242505

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 199

  MichaudMXieXBravo-San PedroJMZitvogelLWhiteEKroemerG. An autophagy-dependent anticancer immune response determines the efficacy of melanoma chemotherapy. Oncoimmunology (2014) 3(7):e944047.10.4161/21624011.2014.944047

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 200

  DemariaSSantoriFRNgBLiebesLFormentiSCVukmanovicS. Select forms of tumor cell apoptosis induce dendritic cell maturation. J Leukoc Biol (2005) 77(3):361–8.10.1189/jlb.0804478

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 201

  SchumacherLYVoDDGarbanHJComin-AnduixBOwensSKDissetteVBet alImmunosensitization of tumor cells to dendritic cell-activated immune responses with the proteasome inhibitor bortezomib (PS-341, Velcade). J Immunol (2006) 176(8):4757–65.10.4049/​jimmunol.176.8.4757

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 202

  ChangCLHsuYTWuCCYangYCWangCWuTCet alImmune mechanism of the antitumor effects generated by bortezomib. J Immunol (2012) 189(6):3209–20.10.4049/jimmunol.1103826

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 203

  van der MostRGCurrieAJMahendranSProsserADarabiARobinsonBWet alTumor eradication after cyclophosphamide depends on concurrent depletion of regulatory T cells: a role for cycling TNFR2-expressing effector-suppressor T cells in limiting effective chemotherapy. Cancer Immunol Immunother (2009) 58(8):1219–28.10.1007/s00262-008-0628-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 204

  ObeidMPanaretakisTJozaNTufiRTesniereAvan EndertPet alCalreticulin exposure is required for the immunogenicity of gamma-irradiation and UVC light-induced apoptosis. Cell Death Differ (2007) 14(10):1848–50.10.1038/sj.cdd.4402201

  • CrossRef
  • Google Scholar

• 205

  Carr-BrendelVMarkovicDSmithMTaylor-PapadimitriouJCohenEP. Immunity to breast cancer in mice immunized with X-irradiated breast cancer cells modified to secrete IL-12. J Immunother (1999) 22(5):415–22.10.1097/00002371-199909000-00005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 206

  StromeSEVossSWilcoxRWakefieldTLTamadaKFliesDet alStrategies for antigen loading of dendritic cells to enhance the antitumor immune response. Cancer Res (2002) 62(6):1884–9.

  • Pubmed Abstract
  • Google Scholar

• 207

  PrasadSJFarrandKJMatthewsSAChangJHMcHughRSRoncheseF. Dendritic cells loaded with stressed tumor cells elicit long-lasting protective tumor immunity in mice depleted of CD4+CD25+ regulatory T cells. J Immunol (2005) 174(1):90–8.10.4049/jimmunol.174.1.90

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 208

  YangHZhouPHuangHChenDMaNCuiQCet alShikonin exerts antitumor activity via proteasome inhibition and cell death induction in vitro and in vivo. Int J Cancer (2009) 124(10):2450–9.10.1002/ijc.24195

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 209

  SharmaPAllisonJP. The future of immune checkpoint therapy. Science (2015) 348(6230):56–61.10.1126/science.aaa8172

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 210

  VineyMLazarouLAbolinsS. The laboratory mouse and wild immunology. Parasite Immunol (2015) 37(5):267–73.10.1111/pim.12150

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 211

  DavisMM. A prescription for human immunology. Immunity (2008) 29(6):835–8.10.1016/j.immuni.2008.12.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 212

  MestasJHughesCC. Of mice and not men: differences between mouse and human immunology. J Immunol (2004) 172(5):2731–8.10.4049/jimmunol.172.5.2731

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 213

  TubianaM. Klaas Breur medal lecture 1985. The growth and progression of human tumors: implications for management strategy. Radiother Oncol (1986) 6(3):167–84.10.1016/S0167-8140(86)80151-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 214

  KleinCA. Parallel progression of primary tumours and metastases. Nat Rev Cancer (2009) 9(4):302–12.10.1038/nrc2627

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 215

  YamazakiTHannaniDPoirier-ColameVLadoireSLocherCSistiguAet alDefective immunogenic cell death of HMGB1-deficient tumors: compensatory therapy with TLR4 agonists. Cell Death Differ (2014) 21(1):69–78.10.1038/cdd.2013.72

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 216

  LoiSPommeySHaibe-KainsBBeavisPADarcyPKSmythMJet alCD73 promotes anthracycline resistance and poor prognosis in triple negative breast cancer. Proc Natl Acad Sci U S A (2013) 110(27):11091–6.10.1073/pnas.1222251110

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 217

  ShalapourSFont-BurgadaJDi CaroGZhongZSanchez-LopezEDharDet alImmunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy. Nature (2015) 521(7550):94–8.10.1038/nature14395

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 218

  De BooSKopeckaJBrusaDGazzanoEMateraLGhigoDet aliNOS activity is necessary for the cytotoxic and immunogenic effects of doxorubicin in human colon cancer cells. Mol Cancer (2009) 8:108.10.1186/1476-4598-8-108

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 219

  RigantiCCastellaBKopeckaJCampiaICosciaMPescarmonaGet alZoledronic acid restores doxorubicin chemosensitivity and immunogenic cell death in multidrug-resistant human cancer cells. PLoS One (2013) 8(4):e60975.10.1371/journal.pone.0060975

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 220

  StollGEnotDMlecnikBGalonJZitvogelLKroemerG. Immune-related gene signatures predict the outcome of neoadjuvant chemotherapy. Oncoimmunology (2014) 3(1):e27884.10.4161/onci.27884

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 221

  PardollDM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer (2012) 12(4):252–64.10.1038/nrc3239

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 222

  GalonJAngellHKBedognettiDMarincolaFM. The continuum of cancer immunosurveillance: prognostic, predictive, and mechanistic signatures. Immunity (2013) 39(1):11–26.10.1016/j.immuni.2013.07.008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 223

  FridmanWHPagesFSautes-FridmanCGalonJ. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer (2012) 12(4):298–306.10.1038/nrc3245

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 224

  ZitvogelLTesniereAKroemerG. Cancer despite immunosurveillance: immunoselection and immunosubversion. Nat Rev Immunol (2006) 6(10):715–27.10.1038/nri1936

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 225

  LadoireSPenault-LlorcaFSenovillaLDalbanCEnotDLocherCet alCombined evaluation of LC3B puncta and HMGB1 expression predicts residual risk of relapse after adjuvant chemotherapy in breast cancer. Autophagy (2015) 11(10):1878–90.10.1080/15548627.2015.1082022

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 226

  KacerovskaDPizingerKMajerFSmidF. Photodynamic therapy of nonmelanoma skin cancer with topical Hypericum perforatum extract – a pilot study. Photochem Photobiol (2008) 84(3):779–85.10.1111/j.1751-1097.2007.00260.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 227

  RookAHWoodGSDuvicMVonderheidECTobiaACabanaB. A phase II placebo-controlled study of photodynamic therapy with topical hypericin and visible light irradiation in the treatment of cutaneous T-cell lymphoma and psoriasis. J Am Acad Dermatol (2010) 63(6):984–90.10.1016/j.jaad.2010.02.039

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 228

  KorenHSchenkGMJindraRHAlthGEbermannRKubinAet alHypericin in phototherapy. J Photochem Photobiol B (1996) 36(2):113–9.10.1016/S1011-1344(96)07357-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 229

  AlecuMUrsaciucCHalalauFComanGMerlevedeWWaelkensEet alPhotodynamic treatment of basal cell carcinoma and squamous cell carcinoma with hypericin. Anticancer Res (1998) 18(6B):4651–4.

  • Pubmed Abstract
  • Google Scholar

• 230

  LiikanenIKoskiAMerisalo-SoikkeliMHemminkiOOksanenMKairemoKet alSerum HMGB1 is a predictive and prognostic biomarker for oncolytic immunotherapy. Oncoimmunology (2015) 4(3):e989771.10.4161/2162402X.2014.989771

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 231

  AgostinisPBergKCengelKAFosterTHGirottiAWGollnickSOet alPhotodynamic therapy of cancer: an update. CA Cancer J Clin (2011) 61(4):250–81.10.3322/caac.20114

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 232

  SuzukiYMimuraKYoshimotoYWatanabeMOhkuboYIzawaSet alImmunogenic tumor cell death induced by chemoradiotherapy in patients with esophageal squamous cell carcinoma. Cancer Res (2012) 72(16):3967–76.10.1158/0008-5472.CAN-12-0851

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 233

  ZappasodiRPupaSMGhediniGCBongarzoneIMagniMCabrasADet alImproved clinical outcome in indolent B-cell lymphoma patients vaccinated with autologous tumor cells experiencing immunogenic death. Cancer Res (2010) 70(22):9062–72.10.1158/0008-5472.CAN-10-1825

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 234

  BaitschLFuertes-MarracoSALegatAMeyerCSpeiserDE. The three main stumbling blocks for anticancer T cells. Trends Immunol (2012) 33(7):364–72.10.1016/j.it.2012.02.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 235

  RedmondWLShermanLA. Peripheral tolerance of CD8 T lymphocytes. Immunity (2005) 22(3):275–84.10.1016/j.immuni.2005.01.010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 236

  ColeDKPumphreyNJBoulterJMSamiMBellJIGostickEet alHuman TCR-binding affinity is governed by MHC class restriction. J Immunol (2007) 178(9):5727–34.10.4049/jimmunol.178.9.5727

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 237

  SchmidDAIrvingMBPosevitzVHebeisenMPosevitz-FejfarASarriaJCet alEvidence for a TCR affinity threshold delimiting maximal CD8 T cell function. J Immunol (2010) 184(9):4936–46.10.4049/jimmunol.1000173

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 238

  ZehnDBevanMJ. T cells with low avidity for a tissue-restricted antigen routinely evade central and peripheral tolerance and cause autoimmunity. Immunity (2006) 25(2):261–70.10.1016/j.immuni.2006.06.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 239

  BaumgaertnerPJandusCRivalsJPDerreLLovgrenTBaitschLet alVaccination-induced functional competence of circulating human tumor-specific CD8 T-cells. Int J Cancer (2012) 130(11):2607–17.10.1002/ijc.26297

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 240

  GubinMMArtyomovMNMardisERSchreiberRD. Tumor neoantigens: building a framework for personalized cancer immunotherapy. J Clin Invest (2015) 125(9):3413–21.10.1172/JCI80008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 241

  SchumacherTNSchreiberRD. Neoantigens in cancer immunotherapy. Science (2015) 348(6230):69–74.10.1126/science.aaa4971

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 242

  Twyman-Saint VictorCRechAJMaityARenganRPaukenKEStelekatiEet alRadiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature (2015) 520(7547):373–7.10.1038/nature14292

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 243

  OchsenbeinAFKlenermanPKarrerULudewigBPericinMHengartnerHet alImmune surveillance against a solid tumor fails because of immunological ignorance. Proc Natl Acad Sci U S A (1999) 96(5):2233–8.10.1073/pnas.96.5.2233

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 244

  Chu-YuanHJingPYi-ShengWHe-PingPHuiYChu-XiongZet alThe impact of chemotherapy-associated neutrophil/lymphocyte counts on prognosis of adjuvant chemotherapy in colorectal cancer. BMC Cancer (2013) 13:177.10.1186/1471-2407-13-177

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 245

  InogesSRodriguez-CalvilloMZabaleguiNLopez-Diaz de CerioAVillanuevaHSoriaEet alClinical benefit associated with idiotypic vaccination in patients with follicular lymphoma. J Natl Cancer Inst (2006) 98(18):1292–301.10.1093/jnci/djj358

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 246

  KakarlaSGottschalkS. CAR T cells for solid tumors: armed and ready to go?Cancer J (2014) 20(2):151–5.10.1097/PPO.0000000000000032

  • Pubmed Abstract
  • CrossRef
  • Google Scholar