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  • Review Article
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Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors

Nature Reviews Clinical Oncology volume 17, pages 725–741 (2020)Cite this article

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Abstract

Conventional chemotherapeutics have been developed into clinically useful agents based on their ability to preferentially kill malignant cells, generally owing to their elevated proliferation rate. Nonetheless, the clinical activity of various chemotherapies is now known to involve the stimulation of anticancer immunity either by initiating the release of immunostimulatory molecules from dying cancer cells or by mediating off-target effects on immune cell populations. Understanding the precise immunological mechanisms that underlie the efficacy of chemotherapy has the potential not only to enable the identification of superior biomarkers of response but also to accelerate the development of synergistic combination regimens that enhance the clinical effectiveness of immune checkpoint inhibitors (ICIs) relative to their effectiveness as monotherapies. Indeed, accumulating evidence supports the clinical value of combining appropriately dosed chemotherapies with ICIs. In this Review, we discuss preclinical and clinical data on the immunostimulatory effects of conventional chemotherapeutics in the context of ICI-based immunotherapy.

Key points

  • The therapeutic efficacy of conventional chemotherapeutic agents involves a considerable immunological component.

  • Conventional chemotherapy can mediate immunostimulatory effects by targeting cancer cells or immune cells as well as by altering whole-body physiology.

  • A range of parameters reflecting the immunological competence of the tumour microenvironment of the patient can influence the efficacy of chemotherapy.

  • Immunostimulatory chemotherapeutics stand out as promising partners for combination regimens involving immune checkpoint inhibitors, although additional research is required to identify the optimal regimens.

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Fig. 1: Principles of immunomodulation by conventional chemotherapeutics.
Fig. 2: Immunogenic cell death prediction scores for chemotherapies with confirmed or potential immunogenic effects.
Fig. 3: Immunological parameters affecting chemotherapy responses in patients with cancer.
Fig. 4: Overview of ongoing clinical trials involving one or more immunogenic cell death inducers in combination with immune checkpoint inhibitors in patients with cancer.

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References

  1. Luo, J., Solimini, N. L. & Elledge, S. J. Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136, 823–837 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Schirrmacher, V. From chemotherapy to biological therapy: a review of novel concepts to reduce the side effects of systemic cancer treatment (Review). Int. J. Oncol. 54, 407–419 (2019).

    CAS  PubMed  Google Scholar 

  3. Galluzzi, L., Buque, A., Kepp, O., Zitvogel, L. & Kroemer, G. Immunological effects of conventional chemotherapy and targeted anticancer agents. Cancer Cell 28, 690–714 (2015).

    Article  CAS  PubMed  Google Scholar 

  4. Zitvogel, L., Pitt, J. M., Daillere, R., Smyth, M. J. & Kroemer, G. Mouse models in oncoimmunology. Nat. Rev. Cancer 16, 759–773 (2016).

    Article  CAS  PubMed  Google Scholar 

  5. Pasquier, E., Kavallaris, M. & Andre, N. Metronomic chemotherapy: new rationale for new directions. Nat. Rev. Clin. Oncol. 7, 455–465 (2010).

    Article  PubMed  Google Scholar 

  6. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    Article  CAS  PubMed  Google Scholar 

  7. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  PubMed  Google Scholar 

  8. Schreiber, R. D., Old, L. J. & Smyth, M. J. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331, 1565–1570 (2011).

    Article  CAS  PubMed  Google Scholar 

  9. Palucka, A. K. & Coussens, L. M. The basis of oncoimmunology. Cell 164, 1233–1247 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Fridman, W. H., Zitvogel, L., Sautes-Fridman, C. & Kroemer, G. The immune contexture in cancer prognosis and treatment. Nat. Rev. Clin. Oncol. 14, 717–734 (2017).

    Article  CAS  PubMed  Google Scholar 

  11. Pages, F. et al. International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet 391, 2128–2139 (2018).

    Article  PubMed  Google Scholar 

  12. Galon, J. & Bruni, D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat. Rev. Drug Discov. 18, 197–218 (2019).

    Article  CAS  PubMed  Google Scholar 

  13. Pfirschke, C. et al. Immunogenic chemotherapy sensitizes tumors to checkpoint blockade therapy. Immunity 44, 343–354 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Mathew, M., Enzler, T., Shu, C. A. & Rizvi, N. A. Combining chemotherapy with PD-1 blockade in NSCLC. Pharmacol. Ther. 186, 130–137 (2018).

    Article  CAS  PubMed  Google Scholar 

  15. Schmid, P. et al. Atezolizumab and Nab-paclitaxel in advanced triple-negative breast cancer. N. Engl. J. Med. 379, 2108–2121 (2018).

    Article  CAS  PubMed  Google Scholar 

  16. Janeway, C. A. Jr., Goodnow, C. C. & Medzhitov, R. Danger - pathogen on the premises! Immunological tolerance. Curr. Biol. 6, 519–522 (1996).

    Article  CAS  PubMed  Google Scholar 

  17. Matzinger, P. The danger model: a renewed sense of self. Science 296, 301–305 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. Klein, L., Robey, E. A. & Hsieh, C. S. Central CD4+ T cell tolerance: deletion versus regulatory T cell differentiation. Nat. Rev. Immunol. 19, 7–18 (2019).

    Article  CAS  PubMed  Google Scholar 

  19. Smith, C. C. et al. Alternative tumour-specific antigens. Nat. Rev. Cancer 19, 465–478 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yarchoan, M., Johnson, B. A. 3rd, Lutz, E. R., Laheru, D. A. & Jaffee, E. M. Targeting neoantigens to augment antitumour immunity. Nat. Rev. Cancer 17, 209–222 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Jones, P. A., Ohtani, H., Chakravarthy, A. & De Carvalho, D. D. Epigenetic therapy in immune-oncology. Nat. Rev. Cancer 19, 151–161 (2019).

    Article  CAS  PubMed  Google Scholar 

  22. Bagchi, A. Unusual nature of long non-coding RNAs coding for “unusual peptides”. Gene 729, 144298 (2020).

    Article  CAS  PubMed  Google Scholar 

  23. Garg, A. D. & Agostinis, P. Cell death and immunity in cancer: From danger signals to mimicry of pathogen defense responses. Immunol. Rev. 280, 126–148 (2017).

    Article  CAS  PubMed  Google Scholar 

  24. Galluzzi, L., Buque, A., Kepp, O., Zitvogel, L. & Kroemer, G. Immunogenic cell death in cancer and infectious disease. Nat. Rev. Immunol. 17, 97–111 (2017).

    Article  CAS  PubMed  Google Scholar 

  25. Gong, T., Liu, L., Jiang, W. & Zhou, R. DAMP-sensing receptors in sterile inflammation and inflammatory diseases. Nat. Rev. Immunol. 20, 95–112 (2020).

    Article  CAS  PubMed  Google Scholar 

  26. Galluzzi, L., Yamazaki, T. & Kroemer, G. Linking cellular stress responses to systemic homeostasis. Nat. Rev. Mol. Cell Biol. 19, 731–745 (2018).

    Article  CAS  PubMed  Google Scholar 

  27. Galluzzi, L. et al. Consensus guidelines for the definition, detection and interpretation of immunogenic cell death. J. Immunother. Cancer 8, e000337 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Bezu, L. et al. eIF2alpha phosphorylation is pathognomonic for immunogenic cell death. Cell Death Differ. 25, 1375–1393 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Pakos-Zebrucka, K. et al. The integrated stress response. EMBO Rep. 17, 1374–1395 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ma, Y. et al. Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells. Immunity 38, 729–741 (2013).

    Article  CAS  PubMed  Google Scholar 

  31. Kasikova, L. et al. Calreticulin exposure correlates with robust adaptive antitumor immunity and favorable prognosis in ovarian carcinoma patients. J. Immunother. Cancer 7, 312 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Wang, Z. et al. cGAS/STING axis mediates a topoisomerase II inhibitor-induced tumor immunogenicity. J. Clin. Invest. 129, 4850–4862 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sistigu, A. et al. Cancer cell-autonomous contribution of type I interferon signaling to the efficacy of chemotherapy. Nat. Med. 20, 1301–1309 (2014).

    Article  CAS  PubMed  Google Scholar 

  34. Liu, M. et al. Dual inhibition of DNA and histone methyltransferases increases viral mimicry in ovarian cancer cells. Cancer Res. 78, 5754–5766 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Rodriguez-Ruiz, M. E. et al. Apoptotic caspases inhibit abscopal responses to radiation and identify a new prognostic biomarker for breast cancer patients. Oncoimmunology 8, e1655964 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Van Hoecke, L. et al. Treatment with mRNA coding for the necroptosis mediator MLKL induces antitumor immunity directed against neo-epitopes. Nat. Commun. 9, 3417 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Yatim, N. et al. RIPK1 and NF-κB signaling in dying cells determines cross-priming of CD8+ T cells. Science 350, 328–334 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Aaes, T. L. et al. Vaccination with necroptotic cancer cells induces efficient anti-tumor immunity. Cell Rep. 15, 274–287 (2016).

    Article  CAS  PubMed  Google Scholar 

  39. Yang, H. et al. Contribution of RIP3 and MLKL to immunogenic cell death signaling in cancer chemotherapy. Oncoimmunology 5, e1149673 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Stoll, G. et al. Pro-necrotic molecules impact local immunosurveillance in human breast cancer. Oncoimmunology 6, e1299302 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Panaretakis, T. et al. Mechanisms of pre-apoptotic calreticulin exposure in immunogenic cell death. EMBO J. 28, 578–590 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Tesniere, A. et al. Immunogenic death of colon cancer cells treated with oxaliplatin. Oncogene 29, 482–491 (2010).

    Article  CAS  PubMed  Google Scholar 

  43. Menger, L. et al. Cardiac glycosides exert anticancer effects by inducing immunogenic cell death. Sci. Transl Med. 4, 143ra199 (2012).

    Article  CAS  Google Scholar 

  44. Liu, P. et al. Crizotinib-induced immunogenic cell death in non-small cell lung cancer. Nat. Commun. 10, 1486 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Humeau, J. et al. Inhibition of transcription by dactinomycin reveals a new characteristic of immunogenic cell stress. EMBO Mol. Med. 12, e11622 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Fucikova, J. et al. Prognostic and predictive value of DAMPs and DAMP-associated processes in cancer. Front. Immunol. 6, 402 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Melief, C. J. M. & Kessler, J. H. Novel insights into the HLA class I immunopeptidome and T-cell immunosurveillance. Genome Med. 9, 44 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Gravett, A. M., Trautwein, N., Stevanovic, S., Dalgleish, A. G. & Copier, J. Gemcitabine alters the proteasome composition and immunopeptidome of tumour cells. Oncoimmunology 7, e1438107 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Galaine, J. et al. CD4 T cells target colorectal cancer antigens upregulated by oxaliplatin. Int. J. Cancer 145, 3112–3125 (2019).

    Article  CAS  PubMed  Google Scholar 

  50. Vanderlugt, C. L. et al. The functional significance of epitope spreading and its regulation by co-stimulatory molecules. Immunol. Rev. 164, 63–72 (1998).

    Article  CAS  PubMed  Google Scholar 

  51. Crawford, J., Dale, D. C. & Lyman, G. H. Chemotherapy-induced neutropenia: risks, consequences, and new directions for its management. Cancer 100, 228–237 (2004).

    Article  PubMed  Google Scholar 

  52. Daniel, D. & Crawford, J. Myelotoxicity from chemotherapy. Semin. Oncol. 33, 74–85 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. Barreto, J. N., McCullough, K. B., Ice, L. L. & Smith, J. A. Antineoplastic agents and the associated myelosuppressive effects: a review. J. Pharm. Pract. 27, 440–446 (2014).

    Article  PubMed  Google Scholar 

  54. Fukuoka, E. et al. Neoadjuvant chemotherapy increases PD-L1 expression and CD8+ tumor-infiltrating lymphocytes in esophageal squamous cell carcinoma. Anticancer Res. 39, 4539–4548 (2019).

    Article  CAS  PubMed  Google Scholar 

  55. Nakashima, K. et al. Immunogenicity of trivalent influenza vaccine in patients with lung cancer undergoing anticancer chemotherapy. Hum. Vaccin. Immunother. 13, 543–550 (2017).

    Article  PubMed  Google Scholar 

  56. Ghosh, A., Politikos, I. & Perales, M. A. Stop and go: hematopoietic cell transplantation in the era of chimeric antigen receptor T cells and checkpoint inhibitors. Curr. Opin. Oncol. 29, 474–483 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Otsubo, D. et al. Early-phase treatment by low-dose 5-fluorouracil or primary tumor resection inhibits MDSC-mediated lung metastasis formation. Anticancer Res. 35, 4425–4431 (2015).

    CAS  PubMed  Google Scholar 

  58. Dimeloe, S. et al. Human regulatory T cells lack the cyclophosphamide-extruding transporter ABCB1 and are more susceptible to cyclophosphamide-induced apoptosis. Eur. J. Immunol. 44, 3614–3620 (2014).

    Article  CAS  PubMed  Google Scholar 

  59. Wanderley, C. W. et al. Paclitaxel reduces tumor growth by reprogramming tumor-associated macrophages to an M1 profile in a TLR4-dependent manner. Cancer Res. 78, 5891–5900 (2018).

    CAS  PubMed  Google Scholar 

  60. Ma, Y. et al. CCL2/CCR2-dependent recruitment of functional antigen-presenting cells into tumors upon chemotherapy. Cancer Res. 74, 436–445 (2014).

    Article  CAS  PubMed  Google Scholar 

  61. Schaer, D. A. et al. The folate pathway inhibitor pemetrexed pleiotropically enhances effects of cancer immunotherapy. Clin. Cancer Res. 25, 7175–7188 (2019).

    Article  CAS  PubMed  Google Scholar 

  62. Ohue, Y. & Nishikawa, H. Regulatory T (Treg) cells in cancer: can Treg cells be a new therapeutic target? Cancer Sci. 110, 2080–2089 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Tongu, M. et al. Metronomic chemotherapy with low-dose cyclophosphamide plus gemcitabine can induce anti-tumor T cell immunity in vivo. Cancer Immunol. Immunother. 62, 383–391 (2013).

    Article  CAS  PubMed  Google Scholar 

  64. Barbon, C. M. et al. Consecutive low doses of cyclophosphamide preferentially target Tregs and potentiate T cell responses induced by DNA PLG microparticle immunization. Cell Immunol. 262,150–161 (2010).

    Article  CAS  PubMed  Google Scholar 

  65. Du, B. & Waxman, D. J. Medium dose intermittent cyclophosphamide induces immunogenic cell death and cancer cell autonomous type I interferon production in glioma models. Cancer Lett. 470,170–180 (2020).

    Article  CAS  PubMed  Google Scholar 

  66. Moschella, F. et al. Unraveling cancer chemoimmunotherapy mechanisms by gene and protein expression profiling of responses to cyclophosphamide. Cancer Res. 71, 3528–3539 (2011).

    Article  CAS  PubMed  Google Scholar 

  67. Buccione, C. et al. Role of interferon regulatory factor 1 in governing Treg depletion, Th1 polarization, inflammasome activation and antitumor efficacy of cyclophosphamide. Int. J. Cancer 142, 976–987 (2018).

    Article  CAS  PubMed  Google Scholar 

  68. Talmadge, J. E. & Gabrilovich, D. I. History of myeloid-derived suppressor cells. Nat. Rev. Cancer 13, 739–752 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Mantovani, A., Marchesi, F., Malesci, A., Laghi, L. & Allavena, P. Tumour-associated macrophages as treatment targets in oncology. Nat. Rev. Clin. Oncol. 14, 399–416 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Le, H. K. et al. Gemcitabine directly inhibits myeloid derived suppressor cells in BALB/c mice bearing 4T1 mammary carcinoma and augments expansion of T cells from tumor-bearing mice. Int. Immunopharmacol. 9, 900–909 (2009).

    Article  CAS  PubMed  Google Scholar 

  71. Vincent, J. et al. 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res. 70, 3052–3061 (2010).

    Article  CAS  PubMed  Google Scholar 

  72. Kodumudi, K. N. et al. A novel chemoimmunomodulating property of docetaxel: suppression of myeloid-derived suppressor cells in tumor bearers. Clin. Cancer Res. 16, 4583–4594 (2010).

    Article  CAS  PubMed  Google Scholar 

  73. Takeuchi, S. et al. Chemotherapy-derived inflammatory responses accelerate the formation of immunosuppressive myeloid cells in the tissue microenvironment of human pancreatic cancer. Cancer Res. 75, 2629–2640 (2015).

    Article  CAS  PubMed  Google Scholar 

  74. Wesolowski, R. et al. Circulating myeloid-derived suppressor cells increase in patients undergoing neo-adjuvant chemotherapy for breast cancer. Cancer Immunol. Immunother. 66, 1437–1447 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Bruchard, M. et al. Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth. Nat. Med. 19, 57–64 (2013).

    Article  CAS  PubMed  Google Scholar 

  76. Buhtoiarov, I. N. et al. Anti-tumour synergy of cytotoxic chemotherapy and anti-CD40 plus CpG-ODN immunotherapy through repolarization of tumour-associated macrophages. Immunology 132, 226–239 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Garg, A. D. et al. Dendritic cell vaccines based on immunogenic cell death elicit danger signals and T cell-driven rejection of high-grade glioma. Sci. Transl Med. 8, 328ra327 (2016).

    Article  CAS  Google Scholar 

  78. Garris, C. S. et al. Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12. Immunity 49, 1148–1161.e7 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Schiavoni, G. et al. Cyclophosphamide synergizes with type I interferons through systemic dendritic cell reactivation and induction of immunogenic tumor apoptosis. Cancer Res. 71, 768–778 (2011).

    Article  CAS  PubMed  Google Scholar 

  80. Tanaka, H., Matsushima, H., Nishibu, A., Clausen, B. E. & Takashima, A. Dual therapeutic efficacy of vinblastine as a unique chemotherapeutic agent capable of inducing dendritic cell maturation. Cancer Res. 69, 6987–6994 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. McDonnell, A. M. et al. Tumor-infiltrating dendritic cells exhibit defective cross-presentation of tumor antigens, but is reversed by chemotherapy. Eur. J. Immunol. 45, 49–59 (2015).

    Article  CAS  PubMed  Google Scholar 

  82. Hong, X. et al. Impact of 5-Fu/oxaliplatin on mouse dendritic cells and synergetic effect with a colon cancer vaccine. Chin. J. Cancer Res. 30, 197–208 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Ervin, S. M., Ramanan, S. V. & Bhatt, A. P. Relationship between the gut microbiome and systemic chemotherapy. Dig. Dis. Sci. 65, 874–884 (2020).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  84. Levy, M., Kolodziejczyk, A. A., Thaiss, C. A. & Elinav, E. Dysbiosis and the immune system. Nat. Rev. Immunol. 17, 219–232 (2017).

    Article  CAS  PubMed  Google Scholar 

  85. Iida, N. et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science 342, 967–970 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Viaud, S. et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 342, 971–976 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Gopalakrishnan, V. et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359, 97–103 (2018).

    Article  CAS  PubMed  Google Scholar 

  88. Routy, B. et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359, 91–97 (2018).

    Article  CAS  PubMed  Google Scholar 

  89. Zitvogel, L., Ma, Y., Raoult, D., Kroemer, G. & Gajewski, T. F. The microbiome in cancer immunotherapy: diagnostic tools and therapeutic strategies. Science 359, 1366–1370 (2018).

    Article  CAS  PubMed  Google Scholar 

  90. Loman, B. R., Jordan, K. R., Haynes, B., Bailey, M. T. & Pyter, L. M. Chemotherapy-induced neuroinflammation is associated with disrupted colonic and bacterial homeostasis in female mice. Sci. Rep. 9, 16490 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Ramakrishna, C. et al. Dominant role of the gut microbiota in chemotherapy induced neuropathic pain. Sci. Rep. 9, 20324 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Wardill, H. R. et al. Irinotecan-induced gastrointestinal dysfunction and pain are mediated by common TLR4-dependent mechanisms. Mol. Cancer Ther. 15, 1376–1386 (2016).

    Article  CAS  PubMed  Google Scholar 

  93. Chang, C. W. et al. Fecal microbiota transplantation prevents intestinal injury, upregulation of toll-like receptors, and 5-fluorouracil/oxaliplatin-induced toxicity in colorectal cancer. Int. J. Mol. Sci. 21, 386 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  94. Alexander, J. L. et al. Gut microbiota modulation of chemotherapy efficacy and toxicity. Nat. Rev. Gastroenterol. Hepatol. 14, 356–365 (2017).

    Article  CAS  PubMed  Google Scholar 

  95. Cordova, M. J., Riba, M. B. & Spiegel, D. Post-traumatic stress disorder and cancer. Lancet Psychiatry 4, 330–338 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Yang, H. et al. Stress-glucocorticoid-TSC22D3 axis compromises therapy-induced antitumor immunity. Nat. Med. 25, 1428–1441 (2019).

    Article  CAS  PubMed  Google Scholar 

  97. Obradovic, M. M. S. et al. Glucocorticoids promote breast cancer metastasis. Nature 567, 540–544 (2019).

    Article  CAS  PubMed  Google Scholar 

  98. Hamy, A. S. et al. Comedications influence immune infiltration and pathological response to neoadjuvant chemotherapy in breast cancer. Oncoimmunology 9, 1677427 (2020).

    Article  PubMed  Google Scholar 

  99. Le, C. P. et al. Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination. Nat. Commun. 7, 10634 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Phadke, S. & Clamon, G. Beta blockade as adjunctive breast cancer therapy: a review. Crit. Rev. Oncol. Hematol. 138, 173–177 (2019).

    Article  PubMed  Google Scholar 

  101. Hiller, J. G. et al. Preoperative β-blockade with propranolol reduces biomarkers of metastasis in breast cancer: a phase II randomized trial. Clin. Cancer Res. 26, 1803–1811 (2020).

    Article  CAS  PubMed  Google Scholar 

  102. Yeung, J. T. et al. LOH in the HLA class I region at 6p21 is associated with shorter survival in newly diagnosed adult glioblastoma. Clin. Cancer Res. 19, 1816–1826 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Sade-Feldman, M. et al. Resistance to checkpoint blockade therapy through inactivation of antigen presentation. Nat. Commun. 8, 1136 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Tsukahara, T. et al. Prognostic significance of HLA class I expression in osteosarcoma defined by anti-pan HLA class I monoclonal antibody, EMR8-5. Cancer Sci. 97, 1374–1380 (2006).

    Article  CAS  PubMed  Google Scholar 

  105. Noblejas-Lopez, M. D. M. et al. Expression of MHC class I, HLA-A and HLA-B identifies immune-activated breast tumors with favorable outcome. Oncoimmunology 8, e1629780 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Ladoire, S. et al. The presence of LC3B puncta and HMGB1 expression in malignant cells correlate with the immune infiltrate in breast cancer. Autophagy 12, 864–875 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Guo, L. et al. Phosphorylated eIF2alpha predicts disease-free survival in triple-negative breast cancer patients. Sci. Rep. 7, 44674 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Fucikova, J. et al. Calreticulin expression in human non-small cell lung cancers correlates with increased accumulation of antitumor immune cells and favorable prognosis. Cancer Res. 76, 1746–1756 (2016).

    Article  CAS  PubMed  Google Scholar 

  109. Fucikova, J. et al. Calreticulin exposure by malignant blasts correlates with robust anticancer immunity and improved clinical outcome in AML patients. Blood 128, 3113–3124 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Truxova, I. et al. Calreticulin exposure on malignant blasts correlates with improved natural killer cell-mediated cytotoxicity in acute myeloid leukemia patients. Haematologica https://doi.org/10.3324/haematol.2019.223933 (2019).

    Article  PubMed  Google Scholar 

  111. Leone, R. D. & Emens, L. A. Targeting adenosine for cancer immunotherapy. J. Immunother. Cancer 6, 57 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Majeti, R. et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell 138, 286–299 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Liu, P. et al. Immunosuppression by mutated calreticulin released from malignant cells. Mol. Cell 77, 748–760.e9 (2020).

    Article  CAS  PubMed  Google Scholar 

  114. Kroemer, G., Senovilla, L., Galluzzi, L., Andre, F. & Zitvogel, L. Natural and therapy-induced immunosurveillance in breast cancer. Nat. Med. 21, 1128–1138 (2015).

    Article  CAS  PubMed  Google Scholar 

  115. Bergmann, C. et al. Toll-like receptor 4 single-nucleotide polymorphisms Asp299Gly and Thr399Ile in head and neck squamous cell carcinomas. J. Transl Med. 9, 139 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Tauriello, D. V. F. et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 554, 538–543 (2018).

    Article  CAS  PubMed  Google Scholar 

  117. Formenti, S. C. et al. Baseline T cell dysfunction by single cell network profiling in metastatic breast cancer patients. J. Immunother. Cancer 7, 177 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Prigerson, H. G. et al. Chemotherapy use, performance status, and quality of life at the end of life. JAMA Oncol. 1, 778–784 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Garon, E. B. et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 372, 2018–2028 (2015).

    Article  PubMed  Google Scholar 

  121. Rosenberg, J. E. et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 387, 1909–1920 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Boutros, C. et al. Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat. Rev. Clin. Oncol. 13, 473–486 (2016).

    Article  CAS  PubMed  Google Scholar 

  123. US National Library of Medicine. Clinical trials.gov https://clinicaltrials.gov/ct2/results?cond=Cancer&term=immune+checkpoint&cntry=&state=&city=&dist=# (2020).

  124. Yamazaki, T., Buque, A., Ames, T. D. & Galluzzi, L. PT-112 induces immunogenic cell death and synergizes with immune checkpoint blockers in mouse tumor models. Oncoimmunology 9, 1721810 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  125. Ladoire, S. et al. Pathologic complete response to neoadjuvant chemotherapy of breast carcinoma is associated with the disappearance of tumor-infiltrating FOXP3+ regulatory T cells. Clin. Cancer Res. 14, 2413–2420 (2008).

    Article  CAS  PubMed  Google Scholar 

  126. Garcia-Martinez, E. et al. Tumor-infiltrating immune cell profiles and their change after neoadjuvant chemotherapy predict response and prognosis of breast cancer. Breast Cancer Res. 16, 488 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Peng, J. et al. Chemotherapy induces programmed cell death-ligand 1 overexpression via the nuclear factor-κB to foster an immunosuppressive tumor microenvironment in ovarian cancer. Cancer Res. 75, 5034–5045 (2015).

    Article  CAS  PubMed  Google Scholar 

  128. Wu, Y. et al. Repeated cycles of 5-fluorouracil chemotherapy impaired anti-tumor functions of cytotoxic T cells in a CT26 tumor-bearing mouse model. BMC Immunol. 17, 29 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Park, S. J. et al. Cisplatin and oxaliplatin induce similar immunogenic changes in preclinical models of head and neck cancer. Oral Oncol. 95, 127–135 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Fournel, L. et al. Cisplatin increases PD-L1 expression and optimizes immune check-point blockade in non-small cell lung cancer. Cancer Lett. 464, 5–14 (2019).

    Article  CAS  PubMed  Google Scholar 

  131. Dosset, M. et al. PD-1/PD-L1 pathway: an adaptive immune resistance mechanism to immunogenic chemotherapy in colorectal cancer. Oncoimmunology 7, e1433981 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Ding, Z. C. et al. Immunosuppressive myeloid cells induced by chemotherapy attenuate antitumor CD4+ T-cell responses through the PD-1-PD-L1 axis. Cancer Res. 74, 3441–3453 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Leduc, C. et al. TPF induction chemotherapy increases PD-L1 expression in tumour cells and immune cells in head and neck squamous cell carcinoma. ESMO Open 3, e000257 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Sakai, H. et al. Impact of cytotoxic chemotherapy on PD-L1 expression in patients with non-small cell lung cancer negative for EGFR mutation and ALK fusion. Lung Cancer 127, 59–65 (2019).

    Article  PubMed  Google Scholar 

  135. Lacour, M. et al. Adjuvant chemotherapy increases programmed death-ligand 1 (PD-L1) expression in non-small cell lung cancer recurrence. Clin. Lung Cancer 20, 391–396 (2019).

    Article  CAS  PubMed  Google Scholar 

  136. Shin, J. et al. Effect of platinum-based chemotherapy on PD-L1 expression on tumor cells in non-small cell lung cancer. Cancer Res. Treat. 51, 1086–1097 (2019).

    Article  CAS  PubMed  Google Scholar 

  137. Grigg, C. & Rizvi, N. A. PD-L1 biomarker testing for non-small cell lung cancer: truth or fiction? J. Immunother. Cancer 4, 48 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Martinez, P., Peters, S., Stammers, T. & Soria, J. C. Immunotherapy for the first-line treatment of patients with metastatic non-small cell lung cancer. Clin. Cancer Res. 25, 2691–2698 (2019).

    Article  CAS  PubMed  Google Scholar 

  139. FDA approves nivolumab plus ipilimumab for first-line mNSCLC (PD-L1 tumor expression ≥1%) https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-nivolumab-plus-ipilimumab-first-line-mnsclc-pd-l1-tumor-expression-1 (2020).

  140. FDA approves nivolumab plus ipilimumab and chemotherapy for first-line treatment of metastatic NSCLC. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-nivolumab-plus-ipilimumab-and-chemotherapy-first-line-treatment-metastatic-nsclc (2020).

  141. Voorwerk, L. et al. Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial. Nat. Med. 25, 920–928 (2019).

    Article  CAS  PubMed  Google Scholar 

  142. Demaria, S., Romano, E., Brackstone, M. & Formenti, S. C. Immune induction strategies to enhance responses to PD-1 blockade: lessons from the TONIC trial. J. Immunother. Cancer 7, 318 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Antonia, S. J. et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N. Engl. J. Med. 377, 1919–1929 (2017).

    Article  CAS  PubMed  Google Scholar 

  144. Socinski, M. A. et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N. Engl. J. Med. 378, 2288–2301 (2018).

    Article  CAS  PubMed  Google Scholar 

  145. Peters, S. et al. Phase II trial of atezolizumab as first-line or subsequent therapy for patients with programmed death-ligand 1-selected advanced non-small-cell lung cancer (BIRCH). J. Clin. Oncol. 35, 2781–2789 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Garassino, M. C. et al. Durvalumab as third-Line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study. Lancet Oncol. 19, 521–536 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Reck, M. et al. Nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of platinum-doublet chemotherapy (chemo) vs 4 cycles chemo as first-line (1L) treatment (tx) for stage IV/recurrent non-small cell lung cancer (NSCLC): CheckMate 9LA. https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl.9501 (2020).

  148. Vanmeerbeek, I. et al. Trial watch: chemotherapy-induced immunogenic cell death in immuno-oncology. Oncoimmunology 9, 1703449 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Chen, R. et al. Pembrolizumab in relapsed or refractory Hodgkin lymphoma: 2-year follow-up of KEYNOTE-087. Blood 134, 1144–1153 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Garg, A. D. et al. ROS-induced autophagy in cancer cells assists in evasion from determinants of immunogenic cell death. Autophagy 9, 1292–1307 (2013).

    Article  CAS  PubMed  Google Scholar 

  151. Yamamoto, K. et al. Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I. Nature 581, 100–105 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Sliter, D. A. et al. Parkin and PINK1 mitigate STING-induced inflammation. Nature 561, 258–262 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Di Virgilio, F., Sarti, A. C., Falzoni, S., De Marchi, E. & Adinolfi, E. Extracellular ATP and P2 purinergic signalling in the tumour microenvironment. Nat. Rev. Cancer 18, 601–618 (2018).

    Article  PubMed  CAS  Google Scholar 

  154. Krysko, D. V. et al. Immunogenic cell death and DAMPs in cancer therapy. Nat. Rev. Cancer 12, 860–875 (2012).

    Article  CAS  PubMed  Google Scholar 

  155. Vanpouille-Box, C., Demaria, S., Formenti, S. C. & Galluzzi, L. Cytosolic DNA sensing in organismal tumor control. Cancer Cell 34, 361–378 (2018).

    Article  CAS  PubMed  Google Scholar 

  156. Lucca, L. E. & Dominguez-Villar, M. Modulation of regulatory T cell function and stability by co-inhibitory receptors. Nat. Rev. Immunol. https://doi.org/10.1038/s41577-020-0296-3 (2020).

    Article  PubMed  Google Scholar 

  157. Mayes, P. A., Hance, K. W. & Hoos, A. The promise and challenges of immune agonist antibody development in cancer. Nat. Rev. Drug Discov. 17, 509–527 (2018).

    Article  CAS  PubMed  Google Scholar 

  158. Fucikova, J. et al. TIM-3 dictates functional orientation of the immune infiltrate in ovarian cancer. Clin. Cancer Res. 25, 4820–4831 (2019).

    Article  CAS  PubMed  Google Scholar 

  159. Creelan, B. C. & Antonia, S. J. The NKG2A immune checkpoint - a new direction in cancer immunotherapy. Nat. Rev. Clin. Oncol. 16, 277–278 (2019).

    Article  CAS  PubMed  Google Scholar 

  160. Conroy, J. M. et al. Next generation sequencing of PD-L1 for predicting response to immune checkpoint inhibitors. J. Immunother. Cancer 7, 18 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Patel, S. P. & Kurzrock, R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol. Cancer Ther. 14, 847–856 (2015).

    Article  CAS  PubMed  Google Scholar 

  162. Vanpouille-Box, C., Hoffmann, J. A. & Galluzzi, L. Pharmacological modulation of nucleic acid sensors - therapeutic potential and persisting obstacles. Nat. Rev. Drug Discov. 18, 845–867 (2019).

    Article  CAS  PubMed  Google Scholar 

  163. Levesque, S. et al. A synergistic triad of chemotherapy, immune checkpoint inhibitors, and caloric restriction mimetics eradicates tumors in mice. Oncoimmunology 8, e1657375 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  164. Hammerich, L. et al. Systemic clinical tumor regressions and potentiation of PD1 blockade with in situ vaccination. Nat. Med. 25, 814–824 (2019).

    Article  CAS  PubMed  Google Scholar 

  165. Sprooten, J. et al. Trial watch: dendritic cell vaccination for cancer immunotherapy. Oncoimmunology 8, e1638212 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  166. Markovic, S. N. et al. Sequencing ipilimumab immunotherapy before or after chemotherapy (Nab-paclitaxel and bevacizumab) for the treatment of BRAFwt (BRAF wild-type) metastatic malignant melanoma: results of a study of academic and community cancer research united (ACCRU) RU261206I. Am. J. Clin. Oncol. 43, 115–121 (2020).

    Article  PubMed  Google Scholar 

  167. Palmer, A. C. & Sorger, P. K. Combination cancer therapy can confer benefit via patient-to-patient variability without drug additivity or synergy. Cell 171, 1678–1691.e13 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Garrido, G. et al. Induction of immunogenic apoptosis by blockade of epidermal growth factor receptor activation with a specific antibody. J. Immunol. 187, 4954–4966 (2011).

    Article  CAS  PubMed  Google Scholar 

  169. Tatsuno, K. et al. Extracorporeal photochemotherapy induces bona fide immunogenic cell death. Cell Death Dis. 10, 578 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  170. Ventura, A. et al. Extracorporeal photochemotherapy drives monocyte-to-dendritic cell maturation to induce anticancer immunity. Cancer Res. 78, 4045–4058 (2018).

    Article  CAS  PubMed  Google Scholar 

  171. Obeid, M. et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat. Med. 13, 54–61 (2007).

    Article  CAS  PubMed  Google Scholar 

  172. Vacchelli, E. et al. Chemotherapy-induced antitumor immunity requires formyl peptide receptor 1. Science 350, 972–978 (2015).

    Article  CAS  PubMed  Google Scholar 

  173. Ma, Y. et al. Contribution of IL-17-producing gamma delta T cells to the efficacy of anticancer chemotherapy. J. Exp. Med. 208, 491–503 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Michaud, M. et al. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 334, 1573–1577 (2011).

    Article  CAS  PubMed  Google Scholar 

  175. Ghiringhelli, F. et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nat. Med. 15, 1170–1178 (2009).

    Article  CAS  PubMed  Google Scholar 

  176. Bugaut, H. et al. Bleomycin exerts ambivalent antitumor immune effect by triggering both immunogenic cell death and proliferation of regulatory T cells. PLoS ONE 8, e65181 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Spisek, R. et al. 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 109, 4839–4845 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Cirone, M. et al. Primary effusion lymphoma cell death induced by bortezomib and AG 490 activates dendritic cells through CD91. PLoS ONE 7, e31732 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Demaria, S. et al. Select forms of tumor cell apoptosis induce dendritic cell maturation. J. Leukoc. Biol. 77, 361–368 (2005).

    Article  CAS  PubMed  Google Scholar 

  180. Pozzi, C. et al. The EGFR-specific antibody cetuximab combined with chemotherapy triggers immunogenic cell death. Nat. Med. 22, 624–631 (2016).

    Article  CAS  PubMed  Google Scholar 

  181. Sun, C. et al. Reactive oxygen species involved in CT26 immunogenic cell death induced by Clostridium difficile toxin B. Immunol. Lett. 164, 65–71 (2015).

    Article  CAS  PubMed  Google Scholar 

  182. Ghiringhelli, F. et al. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol. Immunother. 56, 641–648 (2007).

    Article  CAS  PubMed  Google Scholar 

  183. Viaud, S. et al. Cyclophosphamide induces differentiation of Th17 cells in cancer patients. Cancer Res. 71, 661–665 (2011).

    Article  CAS  PubMed  Google Scholar 

  184. Iida, Y. et al. Contrasting effects of cyclophosphamide on anti-CTL-associated protein 4 blockade therapy in two mouse tumor models. Cancer Sci. 108, 1974–1984 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Orecchioni, S. et al. Vinorelbine, cyclophosphamide and 5-FU effects on the circulating and intratumoural landscape of immune cells improve anti-PD-L1 efficacy in preclinical models of breast cancer and lymphoma. Br. J. Cancer 118, 1329–1336 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Chen, X. et al. Effective chemoimmunotherapy with anti-TGFbeta antibody and cyclophosphamide in a mouse model of breast cancer. PLoS ONE 9, e85398 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  187. Hossain, D. M. S. et al. Dinaciclib induces immunogenic cell death and enhances anti-PD1-mediated tumor suppression. J. Clin. Invest. 128, 644–654 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  188. Zhou, H. et al. Oncolysis with DTT-205 and DTT-304 generates immunological memory in cured animals. Cell Death Dis. 9, 1086 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  189. Nuccitelli, R. et al. Nanoelectroablation of murine tumors triggers a CD8-dependent inhibition of secondary tumor growth. PLoS ONE 10, e0134364 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  190. Nuccitelli, R. et al. Nano-pulse stimulation is a physical modality that can trigger immunogenic tumor cell death. J. Immunother. Cancer 5, 32 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  191. Garg, A. D., Krysko, D. V., Vandenabeele, P. & Agostinis, P. Hypericin-based photodynamic therapy induces surface exposure of damage-associated molecular patterns like HSP70 and calreticulin. Cancer Immunol. Immunother. 61, 215–221 (2012).

    Article  CAS  PubMed  Google Scholar 

  192. Garg, A. D. et al. A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death. EMBO J. 31, 1062–1079 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Wang, M. et al. BET bromodomain inhibitor JQ1 promotes immunogenic cell death in tongue squamous cell carcinoma. Int. Immunopharmacol. 76, 105921 (2019).

    Article  CAS  PubMed  Google Scholar 

  194. Riganti, C. et al. Bromodomain inhibition exerts its therapeutic potential in malignant pleural mesothelioma by promoting immunogenic cell death and changing the tumor immune-environment. Oncoimmunology 7, e1398874 (2018).

    Article  PubMed  Google Scholar 

  195. Camilio, K. A., Rekdal, O. & Sveinbjornsson, B. LTX-315 (Oncopore): a short synthetic anticancer peptide and novel immunotherapeutic agent. Oncoimmunology 3, e29181 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  196. Eike, L. M., Yang, N., Rekdal, O. & Sveinbjornsson, B. The oncolytic peptide LTX-315 induces cell death and DAMP release by mitochondria distortion in human melanoma cells. Oncotarget 6, 34910–34923 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  197. Yamazaki, T. et al. The oncolytic peptide LTX-315 overcomes resistance of cancers to immunotherapy with CTLA4 checkpoint blockade. Cell Death Differ. 23, 1004–1015 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Zhou, H. et al. The oncolytic peptide LTX-315 triggers immunogenic cell death. Cell Death Dis. 7, e2134 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Eike, L. M., Mauseth, B., Camilio, K. A., Rekdal, O. & Sveinbjornsson, B. The cytolytic amphipathic beta(2,2)-amino acid LTX-401 induces DAMP release in melanoma cells and causes complete regression of B16 melanoma. PLoS ONE 11, e0148980 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  200. Mauseth, B. et al. The novel oncolytic compound LTX-401 induces antitumor immune responses in experimental hepatocellular carcinoma. Mol. Ther. Oncolytics 14, 139–148 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Xie, W. et al. Tumor lysis with LTX-401 creates anticancer immunity. Oncoimmunology 8, 1594555 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  202. Zhou, H. et al. The oncolytic compound LTX-401 targets the Golgi apparatus. Cell Death Differ. 23, 2031–2041 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Xie, W. et al. Lurbinectedin synergizes with immune checkpoint blockade to generate anticancer immunity. Oncoimmunology 8, e1656502 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  204. Yu, Z. et al. Treatment of osteosarcoma with microwave thermal ablation to induce immunogenic cell death. Oncotarget 5, 6526–6539 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  205. Koks, C. A. et al. Newcastle disease virotherapy induces long-term survival and tumor-specific immune memory in orthotopic glioma through the induction of immunogenic cell death. Int. J. Cancer 136, E313–E325 (2015).

    Article  CAS  PubMed  Google Scholar 

  206. Zamarin, D. et al. Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci. Transl Med. 6, 226ra232 (2014).

    Article  CAS  Google Scholar 

  207. Van Loenhout, J. et al. Cold atmospheric plasma-treated PBS eliminates immunosuppressive pancreatic stellate cells and induces immunogenic cell death of pancreatic cancer cells. Cancers 11, 1597 (2019).

    Article  PubMed Central  CAS  Google Scholar 

  208. Lin, A. G. et al. Non-thermal plasma induces immunogenic cell death in vivo in murine CT26 colorectal tumors. Oncoimmunology 7, e1484978 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  209. Lin, A. et al. Nanosecond-pulsed DBD plasma-generated reactive oxygen species trigger immunogenic cell death in A549 lung carcinoma cells through intracellular oxidative stress. Int. J. Mol. Sci. 18, 966 (2017).

    Article  PubMed Central  CAS  Google Scholar 

  210. Lin, A. et al. Non-thermal plasma as a unique delivery system of short-lived reactive oxygen and nitrogen species for immunogenic cell death in melanoma cells. Adv. Sci. 6, 1802062 (2019).

    Article  CAS  Google Scholar 

  211. Sagwal, S. K., Pasqual-Melo, G., Bodnar, Y., Gandhirajan, R. K. & Bekeschus, S. Combination of chemotherapy and physical plasma elicits melanoma cell death via upregulation of SLC22A16. Cell Death Dis. 9, 1179 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  212. Azzariti, A. et al. Plasma-activated medium triggers cell death and the presentation of immune activating danger signals in melanoma and pancreatic cancer cells. Sci. Rep. 9, 4099 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  213. Chen, G. et al. Transdermal cold atmospheric plasma-mediated immune checkpoint blockade therapy. Proc. Natl Acad. Sci. USA 117, 3687–3692 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Pietrocola, F. et al. Caloric restriction mimetics enhance anticancer immunosurveillance. Cancer Cell 30, 147–160 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Korbelik, M. & Dougherty, G. J. Photodynamic therapy-mediated immune response against subcutaneous mouse tumors. Cancer Res. 59, 1941–1946 (1999).

    CAS  PubMed  Google Scholar 

  216. Korbelik, M., Stott, B. & Sun, J. Photodynamic therapy-generated vaccines: relevance of tumour cell death expression. Br. J. Cancer 97, 1381–1387 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Korbelik, M., Zhang, W. & Merchant, S. 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. 60, 1431–1437 (2011).

    Article  CAS  PubMed  Google Scholar 

  218. Krosl, G., Korbelik, M. & Dougherty, G. J. Induction of immune cell infiltration into murine SCCVII tumour by photofrin-based photodynamic therapy. Br. J. Cancer 71, 549–555 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Bryce, A. H. et al. PT-112 in advanced metastatic castrate-resistant prostate cancer (mCRPC), as monotherapy or in combination with PD-L1 inhibitor avelumab: findings from two phase I studies. J. Clin. Oncol. 38, https://doi.org/10.1200/JCO.2020.38.6_suppl.83 (2020).

  220. Karp, D. D. et al. PT-112: a well-tolerated novel immunogenic cell death (ICD) inducer with activity in advanced solid tumors. Ann. Oncol. 29 (Suppl. 8), viii133–viii148 (2018).

    Google Scholar 

  221. Demaria, S. et al. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int. J. Radiat. Oncol. Biol. Phys. 58, 862–870 (2004).

    Article  PubMed  Google Scholar 

  222. Formenti, S. C. et al. Radiotherapy induces responses of lung cancer to CTLA-4 blockade. Nat. Med. 24, 1845–1851 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Park, S. S. et al. PD-1 restrains radiotherapy-induced abscopal effect. Cancer Immunol. Res. 3, 610–619 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Herter-Sprie, G. S. et al. Synergy of radiotherapy and PD-1 blockade in Kras-mutant lung cancer. JCI Insight 1, e87415 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  225. Vanpouille-Box, C. et al. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat. Commun. 8, 15618 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  226. Vanpouille-Box, C. et al. TGFbeta is a master regulator of radiation therapy-induced antitumor immunity. Cancer Res. 75, 2232–2242 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Antonia, S. J. et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N. Engl. J. Med. 379, 2342–2350 (2018).

    Article  CAS  PubMed  Google Scholar 

  228. Gomes-da-Silva, L. C. et al. Photodynamic therapy with redaporfin targets the endoplasmic reticulum and Golgi apparatus. EMBO J. 37, e98354 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  229. Sukkurwala, A. Q. et al. Screening of novel immunogenic cell death inducers within the NCI mechanistic diversity set. Oncoimmunology 3, e28473 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  230. Bommareddy, P. K., Zloza, A., Rabkin, S. D. & Kaufman, H. L. Oncolytic virus immunotherapy induces immunogenic cell death and overcomes STING deficiency in melanoma. Oncoimmunology 8, 1591875 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  231. Ribas, A. et al. Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy. Cell 170, 1109–1119.e10 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Obeid, M. et al. Calreticulin exposure is required for the immunogenicity of gamma-irradiation and UVC light-induced apoptosis. Cell Death Differ. 14, 1848–1850 (2007).

    Article  CAS  PubMed  Google Scholar 

  233. Brusa, D. et al. Post-apoptotic tumors are more palatable to dendritic cells and enhance their antigen cross-presentation activity. Vaccine 26, 6422–6432 (2008).

    Article  CAS  PubMed  Google Scholar 

  234. Yang, Y. et al. Wogonin induced calreticulin/annexin A1 exposure dictates the immunogenicity of cancer cells in a PERK/AKT dependent manner. PLoS ONE 7, e50811 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Yamamura, Y. et al. The key role of calreticulin in immunomodulation induced by chemotherapeutic agents. Int. J. Clin. Oncol. 20, 386–394 (2015).

    Article  CAS  PubMed  Google Scholar 

  236. Diaconu, I. et al. Immune response is an important aspect of the antitumor effect produced by a CD40L-encoding oncolytic adenovirus. Cancer Res. 72, 2327–2338 (2012).

    Article  CAS  PubMed  Google Scholar 

  237. Hemminki, O. et al. Immunological data from cancer patients treated with Ad5/3-E2F-Δ24-GMCSF suggests utility for tumor immunotherapy. Oncotarget 6, 4467–4481 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  238. Tanaka, H., Matsushima, H., Mizumoto, N. & Takashima, A. Classification of chemotherapeutic agents based on their differential in vitro effects on dendritic cells. Cancer Res. 69, 6978–6986 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Beltran, J., Ghosh, A. K. & Basu, S. Immunotherapy of tumors with neuroimmune ligand capsaicin. J. Immunol. 178, 3260–3264 (2007).

    Article  CAS  PubMed  Google Scholar 

  240. D’Eliseo, D., Manzi, L. & Velotti, F. Capsaicin as an inducer of damage-associated molecular patterns (DAMPs) of immunogenic cell death (ICD) in human bladder cancer cells. Cell Stress Chaperones 18, 801–808 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  241. Gilardini Montani, M. S. et al. Capsaicin-mediated apoptosis of human bladder cancer cells activates dendritic cells via CD91. Nutrition 31, 578–581 (2015).

    Article  CAS  PubMed  Google Scholar 

  242. Golden, E. B. et al. Radiation fosters dose-dependent and chemotherapy-induced immunogenic cell death. Oncoimmunology 3, e28518 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  243. Ghaffari, A. et al. STING agonist therapy in combination with PD-1 immune checkpoint blockade enhances response to carboplatin chemotherapy in high-grade serous ovarian cancer. Br. J. Cancer 119, 440–449 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Zhu, X., Xu, J., Cai, H. & Lang, J. Carboplatin and programmed death-ligand 1 blockade synergistically produce a similar antitumor effect to carboplatin alone in murine ID8 ovarian cancer model. J. Obstet. Gynaecol. Res. 44, 303–311 (2018).

    Article  CAS  PubMed  Google Scholar 

  245. Tremble, L. F., O’Brien, M. A., Soden, D. M. & Forde, P. F. Electrochemotherapy with cisplatin increases survival and induces immunogenic responses in murine models of lung cancer and colorectal cancer. Cancer Lett. 442, 475–482 (2019).

    Article  CAS  PubMed  Google Scholar 

  246. Beyranvand Nejad, E. et al. Tumor eradication by cisplatin is sustained by CD80/86-mediated costimulation of CD8+ T cells. Cancer Res. 76, 6017–6029 (2016).

    Article  CAS  PubMed  Google Scholar 

  247. Segovia, C. et al. Inhibition of a G9a/DNMT network triggers immune-mediated bladder cancer regression. Nat. Med. 25, 1073–1081 (2019).

    Article  CAS  PubMed  Google Scholar 

  248. Miyamoto, S. et al. Coxsackievirus B3 is an oncolytic virus with immunostimulatory properties that is active against lung adenocarcinoma. Cancer Res. 72, 2609–2621 (2012).

    Article  CAS  PubMed  Google Scholar 

  249. Yang, C. et al. Nano-encapsulated tryptanthrin derivative for combined anticancer therapy via inhibiting indoleamine 2,3-dioxygenase and inducing immunogenic cell death. Nanomedicine 14, 2423–2440 (2019).

    Article  CAS  PubMed  Google Scholar 

  250. Majera, D. et al. Targeting genotoxic and proteotoxic stress-response pathways in human prostate cancer by clinically available PARP inhibitors, vorinostat and disulfiram. Prostate 79, 352–362 (2019).

    Article  CAS  PubMed  Google Scholar 

  251. Zhou, B. et al. Disulfiram combined with copper induces immunosuppression via PD-L1 stabilization in hepatocellular carcinoma. Am. J. Cancer Res. 9, 2442–2455 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  252. You, S. Y. et al. Process of immunogenic cell death caused by disulfiram as the anti-colorectal cancer candidate. Biochem. Biophys. Res. Commun. 513, 891–897 (2019).

    Article  CAS  PubMed  Google Scholar 

  253. Chan, O. T. & Yang, L. X. The immunological effects of taxanes. Cancer Immunol. Immunother. 49, 181–185 (2000).

    Article  CAS  PubMed  Google Scholar 

  254. Senovilla, L. et al. An immunosurveillance mechanism controls cancer cell ploidy. Science 337, 1678–1684 (2012).

    Article  CAS  PubMed  Google Scholar 

  255. Wang, W., Qin, S. & Zhao, L. Docetaxel enhances CD3+ CD56+ cytokine-induced killer cells-mediated killing through inducing tumor cells phenotype modulation. Biomed. Pharmacother. 69, 18–23 (2015).

    Article  CAS  PubMed  Google Scholar 

  256. D’Eliseo, D., Di Renzo, L., Santoni, A. & Velotti, F. Docosahexaenoic acid (DHA) promotes immunogenic apoptosis in human multiple myeloma cells, induces autophagy and inhibits STAT3 in both tumor and dendritic cells. Genes. Cancer 8, 426–437 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  257. Pellicciotta, I., Yang, C. P., Goldberg, G. L. & Shahabi, S. Epothilone B enhances class I HLA and HLA-A2 surface molecule expression in ovarian cancer cells. Gynecol. Oncol. 122, 625–631 (2011).

    Article  CAS  PubMed  Google Scholar 

  258. Suzuki, E., Kapoor, V., Jassar, A. S., Kaiser, L. R. & Albelda, S. M. Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin. Cancer Res. 11, 6713–6721 (2005).

    Article  CAS  PubMed  Google Scholar 

  259. Tongu, M., Harashima, N., Tamada, K., Chen, L. & Harada, M. Intermittent chemotherapy can retain the therapeutic potential of anti-CD137 antibody during the late tumor-bearing state. Cancer Sci. 106, 9–17 (2015).

    Article  CAS  PubMed  Google Scholar 

  260. Zhao, T. et al. Inhibition of HIF-1alpha by PX-478 enhances the anti-tumor effect of gemcitabine by inducing immunogenic cell death in pancreatic ductal adenocarcinoma. Oncotarget 6, 2250–2262 (2015).

    Article  PubMed  Google Scholar 

  261. Fucikova, J. et al. Human tumor cells killed by anthracyclines induce a tumor-specific immune response. Cancer Res. 71, 4821–4833 (2011).

    Article  CAS  PubMed  Google Scholar 

  262. Fucikova, J. et al. High hydrostatic pressure induces immunogenic cell death in human tumor cells. Int. J. Cancer 135, 1165–1177 (2014).

    Article  CAS  PubMed  Google Scholar 

  263. Urbanova, L. et al. High hydrostatic pressure affects antigenic pool in tumor cells: implication for dendritic cell-based cancer immunotherapy. Immunol. Lett. 187, 27–34 (2017).

    Article  CAS  PubMed  Google Scholar 

  264. Mikyskova, R. et al. Dendritic cells pulsed with tumor cells killed by high hydrostatic pressure inhibit prostate tumor growth in TRAMP mice. Oncoimmunology 6, e1362528 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  265. Wernitznig, D. et al. First-in-class ruthenium anticancer drug (KP1339/IT-139) induces an immunogenic cell death signature in colorectal spheroids in vitro. Metallomics 11, 1044–1048 (2019).

    Article  CAS  PubMed  Google Scholar 

  266. Bauzon, M. et al. Maytansine-bearing antibody-drug conjugates induce in vitro hallmarks of immunogenic cell death selectively in antigen-positive target cells. Oncoimmunology 8, e1565859 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  267. Donnelly, O. G. et al. Measles virus causes immunogenic cell death in human melanoma. Gene Ther. 20, 7–15 (2013).

    Article  CAS  PubMed  Google Scholar 

  268. Hardcastle, J. et al. Immunovirotherapy with measles virus strains in combination with anti-PD-1 antibody blockade enhances antitumor activity in glioblastoma treatment. Neuro-oncology 19, 493–502 (2017).

    CAS  PubMed  Google Scholar 

  269. Dudek-Peric, A. M. et al. Antitumor immunity triggered by melphalan is potentiated by melanoma cell surface-associated calreticulin. Cancer Res. 75, 1603–1614 (2015).

    Article  CAS  PubMed  Google Scholar 

  270. Lu, X. et al. Alkylating agent melphalan augments the efficacy of adoptive immunotherapy using tumor-specific CD4+ T cells. J. Immunol. 194, 2011–2021 (2015).

    Article  CAS  PubMed  Google Scholar 

  271. Alagkiozidis, I. et al. Time-dependent cytotoxic drugs selectively cooperate with IL-18 for cancer chemo-immunotherapy. J. Transl Med. 9, 77 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  272. Wong, D. Y., Ong, W. W. & Ang, W. H. Induction of immunogenic cell death by chemotherapeutic platinum complexes. Angew. Chem. 54, 6483–6487 (2015).

    Article  CAS  Google Scholar 

  273. Castiello, L. et al. An optimized retinoic acid-inducible gene I agonist M8 induces immunogenic cell death markers in human cancer cells and dendritic cell activation. Cancer Immunol. Immunother. 68, 1479–1492 (2019).

    Article  CAS  PubMed  Google Scholar 

  274. Kokolus, K. M. et al. Schweinfurthin natural products induce regression of murine melanoma and pair with anti-PD-1 therapy to facilitate durable tumor immunity. Oncoimmunology 8, e1539614 (2019).

    Article  PubMed  Google Scholar 

  275. Chen, H. M. et al. Shikonin induces immunogenic cell death in tumor cells and enhances dendritic cell-based cancer vaccine. Cancer Immunol. Immunother. 61, 1989–2002 (2012).

    Article  CAS  PubMed  Google Scholar 

  276. Lin, T. J. et al. Shikonin-enhanced cell immunogenicity of tumor vaccine is mediated by the differential effects of DAMP components. Mol. Cancer 14, 174 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  277. Martin, S. et al. Concurrent MEK and autophagy inhibition is required to restore cell death associated danger-signalling in Vemurafenib-resistant melanoma cells. Biochem. Pharmacol. 93, 290–304 (2015).

    Article  CAS  PubMed  Google Scholar 

  278. West, A. C. et al. An intact immune system is required for the anticancer activities of histone deacetylase inhibitors. Cancer Res. 73, 7265–7276 (2013).

    Article  CAS  PubMed  Google Scholar 

  279. Sonnemann, J. et al. The histone deacetylase inhibitor vorinostat induces calreticulin exposure in childhood brain tumour cells in vitro. Cancer Chemother. Pharmacol. 66, 611–616 (2010).

    Article  CAS  PubMed  Google Scholar 

  280. Booth, L., Roberts, J. L., Poklepovic, A. & Dent, P. Prior exposure of pancreatic tumors to [sorafenib + vorinostat] enhances the efficacy of an anti-PD-1 antibody. Cancer Biol. Ther. 20, 109–121 (2019).

    Article  CAS  PubMed  Google Scholar 

  281. Fritsch, S., Neumann, S., Schaub, J., Steinbeck, C. & Zielesny, A. ErtlFunctionalGroupsFinder: automated rule-based functional group detection with the chemistry development kit (CDK). J. Cheminform. 11, 37 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

We thank Alain Sauvat (Gustave Roussy Institute, Villejuif, France) for computing the ICD score in Fig. 2. LG is supported by a Breakthrough Level 2 grant from the US Department of Defense, Breast Cancer Research Program (#BC180476P1), by the 2019 Laura Ziskin Prize in Translational Research (#ZP-6177, PI: Formenti) from the Stand Up to Cancer, by a Mantle Cell Lymphoma Research Initiative (MCL-RI, PI: Chen-Kiang) grant from the Leukemia and Lymphoma Society, by a startup grant from the Dept. of Radiation Oncology at Weill Cornell Medicine (New York, US), by a Rapid Response Grant from the Functional Genomics Initiative (New York, US), by industrial collaborations with Lytix (Oslo, Norway) and Phosplatin (New York, US), and by donations from Phosplatin, the Luke Heller TECPR2 Foundation (Boston, US) and Sotio a.s. (Prague, Czech Republic). GK is supported by the Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (ANR) – Projets blancs; ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases; Association pour la recherche sur le cancer; Cancéropôle Ile-de-France; Chancelerie des universités de Paris (Legs Poix), Fondation pour la Recherche Médicale; a donation by Elior; European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR); Gustave Roussy Odyssea, the European Union Horizon 2020 Project Oncobiome; Fondation Carrefour; High-end Foreign Expert Program in China (GDW20171100085 and GDW20181100051), Institut National du Cancer; Inserm (HTE); Institut Universitaire de France; LeDucq Foundation; the LabEx Immuno-Oncology; the RHU Torino Lumière; the Seerave Foundation; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); and the SIRIC Cancer Research and Personalized Medicine (CARPEM).

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Authors and Affiliations

  1. Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA

    Lorenzo Galluzzi & Aitziber Buqué

  2. Sandra and Edward Meyer Cancer Center, New York, NY, USA

    Lorenzo Galluzzi

  3. Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA

    Lorenzo Galluzzi

  4. Department of Dermatology, Yale School of Medicine, New Haven, CT, USA

    Lorenzo Galluzzi

  5. Université de Paris, Paris, France

    Lorenzo Galluzzi, Juliette Humeau & Guido Kroemer

  6. Equipe labellisée par la Ligue contre le cancer, INSERM U1138, Centre de Recherche des Cordeliers, Paris, France

    Juliette Humeau & Guido Kroemer

  7. Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France

    Juliette Humeau & Guido Kroemer

  8. Faculté de Médecine, Université Paris Sud, Paris Saclay, Kremlin Bicêtre, France

    Juliette Humeau & Laurence Zitvogel

  9. Gustave Roussy Cancer Campus, Villejuif, France

    Laurence Zitvogel

  10. INSERM U1015, Villejuif, France

    Laurence Zitvogel

  11. Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China

    Guido Kroemer

  12. Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France

    Guido Kroemer

  13. Karolinska Institute, Department of Women’s and Children’s Health, Karolinska University Hospital, Stockholm, Sweden

    Guido Kroemer

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  1. Lorenzo Galluzzi
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Contributions

L.G., J.H., A.B. and G.K. researched data for this article. L.G., L.Z. and G.K. made a substantial contribution to discussions of content. LG and GK wrote the manuscript. All authors edited, reviewed and approved the manuscript prior to submission.

Corresponding authors

Correspondence to Lorenzo Galluzzi or Guido Kroemer.

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Competing interests

L.G. declares consultancy fees from Astra Zeneca, Inzen, the Luke Heller TECPR2 Foundation, and OmniSEQ and is a member of the Scientific Advisory Committee of Boehringer Ingelheim, The Longevity Labs and OmniSEQ. L.Z. is a scientific co-founder of everImmune. G.K. has conducted contract research for Bayer Healthcare, Genentech, Glaxo Smyth Kline, Institut Mérieux, Kaleido, Lytix Pharma, Nucana, Oncolinx, PharmaMar, Samsara, Sotio and Vasculox, is on the Board of Directors of the Bristol Myers Squibb Foundation France, and is a scientific co-founder of everImmune, Samsara Therapeutics and Therafast Bio. J.H. and A.B. declare no competing interests.

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Galluzzi, L., Humeau, J., Buqué, A. et al. Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors. Nat Rev Clin Oncol 17, 725–741 (2020). https://doi.org/10.1038/s41571-020-0413-z

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