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Targeting innate sensing in the tumor microenvironment to improve immunotherapy

Cellular & Molecular Immunology volume 17, pages 13–26 (2020)Cite this article

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Abstract

The innate immune sensing pathways play critical roles in the defense against pathogen infection, but their roles in cancer immunosurveillance and cancer therapies are less defined. We propose that defective innate immune sensing inside the tumor microenvironment might limit T-cell responses to immunotherapy. A recent mechanistic understanding of conventional therapies revealed that both innate immune sensing and T-cell responses are essential for optimal antitumor efficacy. T-cell-based immunotherapy, particularly immune checkpoint blockade, has achieved great success in reactivating antitumor immune responses to lead to tumor regression, but only in a small fraction of patients. Therefore, incorporating conventional therapy that can increase innate sensing and immunotherapy should lead to promising strategies for cancer patients. Here, we review the innate sensing pathways related to cancer initiation/progression and therapies, summarize the recent key findings in innate immune sensing related to conventional therapies, evaluate current combination strategies, and highlight the potential issues of combinational therapies in terms of antitumor efficacy and toxicities.

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Fig. 1: Innate immune sensing pathways and cancer.
Fig. 2: Immune-based mechanisms of conventional therapies and the rationale of combinational therapy.

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References

  1. Janeway, C. A. Jr. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb. Symp. Quant. Biol. 54(Pt 1), 1–13 (1989).

    CAS  PubMed  Google Scholar 

  2. Takeuchi, O. & Akira, S. Pathogen recognition by innate immunity. Arerugi 56, 558–562 (2007).

    CAS  PubMed  Google Scholar 

  3. Iwasaki, A. & Medzhitov, R. Toll-like receptor control of the adaptive immune responses. Nat. Immunol. 5, 987–995 (2004).

    CAS  PubMed  Google Scholar 

  4. Pasare, C. & Medzhitov, R. Toll-like receptors: linking innate and adaptive immunity. Adv. Exp. Med. Biol. 560, 11–18 (2005).

    CAS  PubMed  Google Scholar 

  5. Rakoff-Nahoum, S. & Medzhitov, R. Toll-like receptors and cancer. Nat. Rev. Cancer 9, 57–63 (2009).

    CAS  PubMed  Google Scholar 

  6. Dunn, G. P., Bruce, A. T., Ikeda, H., Old, L. J. & Schreiber, R. D. Cancer immunoediting: from immunosurveillance to tumor escape. Nat. Immunol. 3, 991–998 (2002).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  8. Mittal, D., Gubin, M. M., Schreiber, R. D. & Smyth, M. J. New insights into cancer immunoediting and its three component phases elimination, equilibrium and escape. Curr. Opin. Immunol. 27, 16–25 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Corrales, L., Matson, V., Flood, B., Spranger, S. & Gajewski, T. F. Innate immune signaling and regulation in cancer immunotherapy. Cell Res. 27, 96–108 (2017).

    CAS  PubMed  Google Scholar 

  10. Hamid, O. et al. A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J. Transl. Med. 9, https://doi.org/10.1186/1479-5876-9-204 (2011).

  11. Rusakiewicz, S. et al. Immune infiltrates are prognostic factors in localized gastrointestinal stromal tumors. Cancer Res. 73, 3499–3510 (2013).

    CAS  PubMed  Google Scholar 

  12. Mahmoud, S. M. A. et al. Tumor-infiltrating CD8(+) lymphocytes predict clinical outcome in breast cancer. J. Clin. Oncol. 29, 1949–1955 (2011).

    PubMed  Google Scholar 

  13. Woo, J. W. et al. Tumour-infiltrating CD8+lymphocytes after primary systemic therapy predict clinical outcome in patients with breast cancer. Virchows Arch. 473, S54–S55 (2018).

    Google Scholar 

  14. Azimi, F. et al. Tumor-infiltrating lymphocyte grade is an independent predictor of sentinel lymph node status and survival in patients with cutaneous melanoma. J. Clin. Oncol. 30, 2678–2683 (2012).

    PubMed  Google Scholar 

  15. Mlecnik, B. et al. Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. J. Clin. Oncol. 29, 610–618 (2011).

    PubMed  Google Scholar 

  16. Pages, F. et al. Immune infiltration in human tumors: a prognostic factor that should not be ignored. Oncogene 29, 1093–1102 (2010).

    CAS  PubMed  Google Scholar 

  17. Bogolyubova, A. V. & Belousov, P. V. Inflammatory immune infiltration in human tumors: role in pathogenesis and prognostic and diagnostic value. Biochemistry 81, 1261–1273 (2016).

    CAS  PubMed  Google Scholar 

  18. Arruebo, M. et al. Assessment of the evolution of cancer treatment therapies. Cancers 3, 3279–3330 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Baudino, T. A. Targeted cancer therapy: the next generation of cancer treatment. Curr. Drug Discov. Technol. 12, 3–20 (2015).

    CAS  PubMed  Google Scholar 

  20. Padma, V. V. An overview of targeted cancer therapy. Biomedicine 5, 19 (2015).

    PubMed  PubMed Central  Google Scholar 

  21. Bracci, L., Schiavoni, G., Sistigu, A. & Belardelli, F. Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer. Cell Death Differ. 21, 15–25 (2014).

    CAS  PubMed  Google Scholar 

  22. Baskar, R., Dai, J., Wenlong, N., Yeo, R. & Yeoh, K. W. Biological response of cancer cells to radiation treatment. Front. Mol. Biosci. 1, 24 (2014).

    PubMed  PubMed Central  Google Scholar 

  23. Liu, Z. et al. Hypofractionated EGFR tyrosine kinase inhibitor limits tumor relapse through triggering innate and adaptive immunity. Sci Immunol 4, https://doi.org/10.1126/sciimmunol.aav6473 (2019).

    CAS  PubMed  Google Scholar 

  24. Park, S. et al. The therapeutic effect of Anti-HER2/neu antibody depends on both innate and adaptive immunity. Cancer Cell 18, 160–170 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Deng, L. et al. Damage to nucleic acid sensing: a strategy to enhance radiation therapy. Clin. Cancer Res. 22, 20–25 (2016).

    PubMed  Google Scholar 

  26. Deng, L. et al. STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity 41, 843–852 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Apetoh, L. et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat. Med. 13, 1050–1059 (2007).

    CAS  PubMed  Google Scholar 

  28. Wargo, J. A., Cooper, Z. A. & Flaherty, K. T. Universes collide: combining immunotherapy with targeted therapy for cancer. Cancer Discov. 4, 1377–1386 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Ribas, A. Adaptive immune resistance: how cancer protects from immune attack. Cancer Discov. 5, 915–919 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Tang, H., Qiao, J. & Fu, Y. X. Immunotherapy and tumor microenvironment. Cancer Lett. 370, 85–90 (2016).

    CAS  PubMed  Google Scholar 

  32. Topalian, S. L. et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J. Clin. Oncol. 32, 1020–1030 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Simone, C. B., Burri, S. H. & Heinzerling, J. H. Novel radiotherapy approaches for lung cancer: combining radiation therapy with targeted and immunotherapies. Transl. Lung Cancer R. 4, 545–552 (2015).

    CAS  Google Scholar 

  34. Gotwals, P. et al. Prospects for combining targeted and conventional cancer therapy with immunotherapy. Nat. Rev. Cancer 17, 286–301 (2017).

    CAS  PubMed  Google Scholar 

  35. Zappasodi, R., Merghoub, T. & Wolchok, J. D. Emerging concepts for immune checkpoint blockade-based combination therapies. Cancer Cell 33, 581–598 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Robert, L., Ribas, A. & Hu-Lieskovan, S. Combining targeted therapy with immunotherapy. Can 1+1 equal more than 2? Semin. Immunol. 28, 73–80 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Beutler, B. Toll-like receptors: how they work and what they do. Curr. Opin. Hematol. 9, 2–10 (2002).

    PubMed  Google Scholar 

  38. Kawai, T. & Akira, S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat. Immunol. 11, 373–384 (2010).

    CAS  PubMed  Google Scholar 

  39. Kawasaki, T. & Kawai, T. Toll-like receptor signaling pathways. Front. Immunol. 5, 461 (2014).

    PubMed  PubMed Central  Google Scholar 

  40. O'Neill, L. A., Fitzgerald, K. A. & Bowie, A. G. The Toll-IL-1 receptor adaptor family grows to five members. Trends Immunol. 24, 286–290 (2003).

    PubMed  Google Scholar 

  41. West, A. P., Koblansky, A. A. & Ghosh, S. Recognition and signaling by toll-like receptors. Annu. Rev. Cell Dev. Biol. 22, 409–437 (2006).

    CAS  PubMed  Google Scholar 

  42. Uematsu, S. & Akira, S. Toll-like receptors and innate immunity. J. Mol. Med. 84, 712–725 (2006).

    CAS  PubMed  Google Scholar 

  43. Cui, J., Chen, Y., Wang, H. Y. & Wang, R. F. Mechanisms and pathways of innate immune activation and regulation in health and cancer. Hum. Vaccin Immunother. 10, 3270–3285 (2014).

    PubMed  Google Scholar 

  44. Castano-Rodriguez, N., Kaakoush, N. O. & Mitchell, H. M. Pattern-recognition receptors and gastric cancer. Front. Immunol. 5, 336 (2014).

    PubMed  PubMed Central  Google Scholar 

  45. Huang, B., Zhao, J., Unkeless, J. C., Feng, Z. H. & Xiong, H. TLR signaling by tumor and immune cells: a double-edged sword. Oncogene 27, 218–224 (2008).

    CAS  PubMed  Google Scholar 

  46. Luo, J. L., Maeda, S., Hsu, L. C., Yagita, H. & Karin, M. Inhibition of NF-kappaB in cancer cells converts inflammation- induced tumor growth mediated by TNFalpha to TRAIL-mediated tumor regression. Cancer Cell 6, 297–305 (2004).

    CAS  PubMed  Google Scholar 

  47. Harmey, J. H. et al. Lipopolysaccharide-induced metastatic growth is associated with increased angiogenesis, vascular permeability and tumor cell invasion. Int. J. Cancer 101, 415–422 (2002).

    CAS  PubMed  Google Scholar 

  48. Cen, X., Liu, S. & Cheng, K. The role of Toll-like receptor in inflammation and tumor immunity. Front. Pharm. 9, 878 (2018).

    Google Scholar 

  49. Clarke, S. R. The critical role of CD40/CD40L in the CD4-dependent generation of CD8+ T cell immunity. J. Leukoc. Biol. 67, 607–614 (2000).

    CAS  PubMed  Google Scholar 

  50. Chi, H. et al. Anti-tumor Activity of Toll-like receptor 7 agonists. Front. Pharm. 8, 304 (2017).

    Google Scholar 

  51. Vacchelli, E. et al. Trial watch: FDA-approved Toll-like receptor agonists for cancer therapy. Oncoimmunology 1, 894–907 (2012).

    PubMed  PubMed Central  Google Scholar 

  52. Hoffman, E. S., Smith, R. E. & Renaud, R. C. Jr. From the analyst's couch: TLR-targeted therapeutics. Nat. Rev. Drug Discov. 4, 879–880 (2005).

    CAS  PubMed  Google Scholar 

  53. Hancz, D. et al. Flagellin increases death receptor-mediated cell death in a RIP1-dependent manner. Immunol. Lett. 193, 42–50 (2018).

    CAS  PubMed  Google Scholar 

  54. Takaki, H., Shime, H., Matsumoto, M. & Seya, T. Tumor cell death by pattern-sensing of exogenous RNA: Tumor cell TLR3 directly induces necroptosis by poly(I:C) in vivo, independent of immune effector-mediated tumor shrinkage. Oncoimmunology 6, e1078968 (2017).

    PubMed  Google Scholar 

  55. Dambuza, I. M. & Brown, G. D. C-type lectins in immunity: recent developments. Curr. Opin. Immunol. 32, 21–27 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Drickamer, K. & Fadden, A. J. Genomic analysis of C-type lectins. Biochem. Soc. Symp. 69, 59–72 (2002).

  57. Zelensky, A. N. & Gready, J. E. The C-type lectin-like domain superfamily. FEBS J. 272, 6179–6217 (2005).

    CAS  PubMed  Google Scholar 

  58. Hardison, S. E. & Brown, G. D. C-type lectin receptors orchestrate antifungal immunity. Nat. Immunol. 13, 817–822 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Sancho, D. & Reis e Sousa, C. Signaling by myeloid C-type lectin receptors in immunity and homeostasis. Annu. Rev. Immunol. 30, 491–529 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Kerrigan, A. M. & Brown, G. D. Syk-coupled C-type lectins in immunity. Trends Immunol. 32, 151–156 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Del Fresno, C., Iborra, S., Saz-Leal, P., Martinez-Lopez, M. & Sancho, D. Flexible signaling of myeloid C-type lectin receptors in immunity and inflammation. Front. Immunol. 9, 804 (2018).

    PubMed  PubMed Central  Google Scholar 

  62. Drummond, R. A. & Brown, G. D. Signalling C-type lectins in antimicrobial immunity. PLoS Pathog. 9, e1003417 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Redelinghuys, P. & Brown, G. D. Inhibitory C-type lectin receptors in myeloid cells. Immunol. Lett. 136, 1–12 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Geijtenbeek, T. B. & Gringhuis, S. I. Signalling through C-type lectin receptors: shaping immune responses. Nat. Rev. Immunol. 9, 465–479 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Nonaka, M. et al. Glycosylation-dependent interactions of C-type lectin DC-SIGN with colorectal tumor-associated Lewis glycans impair the function and differentiation of monocyte-derived dendritic cells. J. Immunol. 180, 3347–3356 (2008).

    CAS  PubMed  Google Scholar 

  66. Aarnoudse, C. A., Garcia Vallejo, J. J., Saeland, E. & van Kooyk, Y. Recognition of tumor glycans by antigen-presenting cells. Curr. Opin. Immunol. 18, 105–111 (2006).

    CAS  PubMed  Google Scholar 

  67. Leibundgut-Landmann, S., Osorio, F. & Brown, G. D. & Reis e Sousa, C. Stimulation of dendritic cells via the dectin-1/Syk pathway allows priming of cytotoxic T-cell responses. Blood 112, 4971–4980 (2008).

    CAS  PubMed  Google Scholar 

  68. Napoletano, C. et al. Targeting of macrophage galactose-type C-type lectin (MGL) induces DC signaling and activation. Eur. J. Immunol. 42, 936–945 (2012).

    CAS  PubMed  Google Scholar 

  69. Yan, H., Ohno, N. & Tsuji, N. M. The role of C-type lectin receptors in immune homeostasis. Int. Immunopharmacol. 16, 353–357 (2013).

    CAS  PubMed  Google Scholar 

  70. Noy, R. & Pollard, J. W. Tumor-associated macrophages: from mechanisms to therapy. Immunity 41, 49–61 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Allavena, P. et al. Engagement of the mannose receptor by tumoral mucins activates an immune suppressive phenotype in human tumor-associated macrophages. Clin. Dev. Immunol. 2010, 547179 (2010).

    CAS  PubMed  Google Scholar 

  72. Tian, J. et al. Beta-glucan enhances antitumor immune responses by regulating differentiation and function of monocytic myeloid-derived suppressor cells. Eur. J. Immunol. 43, 1220–1230 (2013).

    CAS  PubMed  Google Scholar 

  73. Masuda, Y., Inoue, M., Miyata, A., Mizuno, S. & Nanba, H. Maitake beta-glucan enhances therapeutic effect and reduces myelosupression and nephrotoxicity of cisplatin in mice. Int. Immunopharmacol. 9, 620–626 (2009).

    CAS  PubMed  Google Scholar 

  74. Liu, Z., Zhou, H., Wang, W., Fu, Y. X. & Zhu, M. A novel dendritic cell targeting HPV16 E7 synthetic vaccine in combination with PD-L1 blockade elicits therapeutic antitumor immunity in mice. Oncoimmunology 5, e1147641 (2016).

    PubMed  PubMed Central  Google Scholar 

  75. Liu, Z. et al. A novel method for synthetic vaccine construction based on protein assembly. Sci. Rep. 4, 7266 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Park, H. Y. et al. Enhancing vaccine antibody responses by targeting Clec9A on dendritic cells. NPJ Vaccines 2, 31 (2017).

    PubMed  PubMed Central  Google Scholar 

  77. Tacken, P. J., Torensma, R. & Figdor, C. G. Targeting antigens to dendritic cells in vivo. Immunobiology 211, 599–608 (2006).

    CAS  PubMed  Google Scholar 

  78. Meylan, E., Tschopp, J. & Karin, M. Intracellular pattern recognition receptors in the host response. Nature 442, 39–44 (2006).

    CAS  PubMed  Google Scholar 

  79. Elinav, E., Strowig, T., Henao-Mejia, J. & Flavell, R. A. Regulation of the antimicrobial response by NLR proteins. Immunity 34, 665–679 (2011).

    CAS  PubMed  Google Scholar 

  80. Saxena, M. & Yeretssian, G. NOD-like receptors: master regulators of inflammation and cancer. Front. Immunol. 5, 327 (2014).

    PubMed  PubMed Central  Google Scholar 

  81. Chen, G., Shaw, M. H., Kim, Y. G. & Nunez, G. NOD-like receptors: role in innate immunity and inflammatory disease. Annu. Rev. Pathol. 4, 365–398 (2009).

    CAS  PubMed  Google Scholar 

  82. Franchi, L., Munoz-Planillo, R. & Nunez, G. Sensing and reacting to microbes through the inflammasomes. Nat. Immunol. 13, 325–332 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Bergsbaken, T., Fink, S. L. & Cookson, B. T. Pyroptosis: host cell death and inflammation. Nat. Rev. Microbiol. 7, 99–109 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Martinon, F., Petrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241 (2006).

    CAS  PubMed  Google Scholar 

  85. Agostini, L. et al. NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity 20, 319–325 (2004).

    CAS  PubMed  Google Scholar 

  86. Couturier-Maillard, A. et al. NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer. J. Clin. Investig. 123, 700–711 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Chen, G. Y., Shaw, M. H., Redondo, G. & Nunez, G. The innate immune receptor Nod1 protects the intestine from inflammation-induced tumorigenesis. Cancer Res. 68, 10060–10067 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Millrud, C. R. et al. Nod-like receptors in head and neck squamous cell carcinoma. Acta Otolaryngol. 133, 1333–1344 (2013).

    CAS  PubMed  Google Scholar 

  89. Cook, G. P., Savic, S., Wittmann, M. & McDermott, M. F. The NLRP3 inflammasome, a target for therapy in diverse disease states. Eur. J. Immunol. 40, 631–634 (2010).

    CAS  PubMed  Google Scholar 

  90. 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).

    CAS  PubMed  Google Scholar 

  91. Chow, M. T. et al. NLRP3 suppresses NK cell-mediated responses to carcinogen-induced tumors and metastases. Cancer Res. 72, 5721–5732 (2012).

    CAS  PubMed  Google Scholar 

  92. Wei, Q. et al. Deregulation of the NLRP3 inflammasome in hepatic parenchymal cells during liver cancer progression. Lab. Investig. 94, 52–62 (2014).

    CAS  PubMed  Google Scholar 

  93. Zaki, M. H. et al. The NOD-like receptor NLRP12 attenuates colon inflammation and tumorigenesis. Cancer Cell 20, 649–660 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Normand, S. et al. Nod-like receptor pyrin domain-containing protein 6 (NLRP6) controls epithelial self-renewal and colorectal carcinogenesis upon injury. Proc. Natl Acad. Sci. USA 108, 9601–9606 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Hu, B. et al. Inflammation-induced tumorigenesis in the colon is regulated by caspase-1 and NLRC4. Proc. Natl Acad. Sci. USA 107, 21635–21640 (2010).

    PubMed  PubMed Central  Google Scholar 

  96. Paludan, S. R. & Bowie, A. G. Immune sensing of DNA. Immunity 38, 870–880 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Yoneyama, M. et al. Viral RNA dedetection by RIG-I-like receptors. Curr. Opin. Immunol. 32, 48–53 (2015).

    CAS  PubMed  Google Scholar 

  98. Ishikawa, H., Ma, Z. & Barber, G. N. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461, 788–792 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Wu, J. et al. Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science 339, 826–830 (2013).

    CAS  PubMed  Google Scholar 

  100. Ferguson, B. J., Mansur, D. S., Peters, N. E., Ren, H. & Smith, G. L. DNA-PK is a DNA sensor for IRF-3-dependent innate immunity. eLife 1, e00047 (2012).

    PubMed  PubMed Central  Google Scholar 

  101. Schlee, M. Master sensors of pathogenic RNA - RIG-I like receptors. Immunobiology 218, 1322–1335 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Woo, S. R. et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 41, 830–842 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Duewell, P. et al. RIG-I-like helicases induce immunogenic cell death of pancreatic cancer cells and sensitize tumors toward killing by CD8(+) T cells. Cell Death Differ. 21, 1825–1837 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Bu, Y., Liu, F., Jia, Q. A. & Yu, S. N. Decreased expression of TMEM173 predicts poor prognosis in patients with hepatocellular carcinoma. PLoS ONE 11, e0165681 (2016).

    PubMed  PubMed Central  Google Scholar 

  105. Lemos, H. et al. STING promotes the growth of tumors characterized by low antigenicity via IDO activation. Cancer Res. 76, 2076–2081 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Hu, J. et al. Dose dependent activation of retinoic acid-inducible gene-I promotes both proliferation and apoptosis signals in human head and neck squamous cell carcinoma. PLoS ONE 8, e58273 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Pestka, S., Krause, C. D. & Walter, M. R. Interferons, interferon-like cytokines, and their receptors. Immunol. Rev. 202, 8–32 (2004).

    CAS  PubMed  Google Scholar 

  108. Fuertes, M. B., Woo, S. R., Burnett, B., Fu, Y. X. & Gajewski, T. F. Type I interferon response and innate immune sensing of cancer. Trends Immunol. 34, 67–73 (2013).

    CAS  PubMed  Google Scholar 

  109. Rathinam, V. A. & Fitzgerald, K. A. Cytosolic surveillance and antiviral immunity. Curr. Opin. Virol. 1, 455–462 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Platanias, L. C. Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat. Rev. Immunol. 5, 375–386 (2005).

    CAS  PubMed  Google Scholar 

  111. Hervas-Stubbs, S. et al. Direct effects of type I interferons on cells of the immune system. Clin. Cancer Res. 17, 2619–2627 (2011).

    CAS  PubMed  Google Scholar 

  112. Lorenzi, S. et al. Type I IFNs control antigen retention and survival of CD8alpha(+) dendritic cells after uptake of tumor apoptotic cells leading to cross-priming. J. Immunol. 186, 5142–5150 (2011).

    CAS  PubMed  Google Scholar 

  113. Curtsinger, J. M. et al. IFNs provide a third signal to CD8 T cells to stimulate clonal expansion and differentiation. J. Immunol. 174, 4465–4469 (2005).

    CAS  PubMed  Google Scholar 

  114. Dunn, G. P., Koebel, C. M. & Schreiber, R. D. Interferons, immunity and cancer immunoediting. Nat. Rev. Immunol. 6, 836–848 (2006).

    CAS  PubMed  Google Scholar 

  115. Dunn, G. P. et al. A critical function for type I interferons in cancer immunoediting. Nat. Immunol. 6, 722–729 (2005).

    CAS  PubMed  Google Scholar 

  116. Fuertes, M. B. et al. Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8{alpha}+ dendritic cells. J. Exp. Med. 208, 2005–2016 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Medrano, R. F. V., Hunger, A., Mendonca, S. A., Barbuto, J. A. M. & Strauss, B. E. Immunomodulatory and antitumor effects of type I interferons and their application in cancer therapy. Oncotarget 8, 71249–71284 (2017).

    PubMed  PubMed Central  Google Scholar 

  118. Moschos, S. J. et al. Neoadjuvant treatment of regional stage IIIB melanoma with high-dose interferon alfa-2b induces objective tumor regression in association with modulation of tumor infiltrating host cellular immune responses. J. Clin. Oncol. 24, 3164–3171 (2006).

    CAS  PubMed  Google Scholar 

  119. Liang, Y. et al. Targeting IFNalpha to tumor by anti-PD-L1 creates feedforward antitumor responses to overcome checkpoint blockade resistance. Nat. Commun. 9, 4586 (2018).

    PubMed  PubMed Central  Google Scholar 

  120. Yang, X. et al. Targeting the tumor microenvironment with interferon-beta bridges innate and adaptive immune responses. Cancer Cell 25, 37–48 (2014).

    PubMed  PubMed Central  Google Scholar 

  121. Michelle Xu, M., Pu, Y., Weichselbaum, R. R. & Fu, Y. X. Integrating conventional and antibody-based targeted anticancer treatment into immunotherapy. Oncogene 36, 585–592 (2017).

    CAS  PubMed  Google Scholar 

  122. Xu, M. M., Pu, Y., Zhang, Y. & Fu, Y. X. The Role of Adaptive Immunity in the Efficacy of Targeted Cancer Therapies. Trends Immunol. 37, 141–153 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Baskar, R., Lee, K. A., Yeo, R. & Yeoh, K.-W. Cancer and radiation therapy: current advances and future directions. Int. J. Med. Sci. 9, 193 (2012).

    PubMed  PubMed Central  Google Scholar 

  124. Hoskin, P. J. & Bhattacharya, I. S. Protons and more: state of the art in radiotherapy. Clin. Med. 14, s61–s65 (2014).

    Google Scholar 

  125. Srinivas, U. S., Tan, B., Vellayappan, B. A. & Jeyasekharan, A. D. ROS and the DNA damage response in cancer. Redox biology.25, 101084 (2018).

  126. Lee, Y. et al. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood 114, 589–595 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Reits, E. A. et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J. Exp. Med. 203, 1259–1271 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  129. Wu, Y., Wu, X., Wu, L., Wang, X. & Liu, Z. The anticancer functions of RIG-I–like receptors, RIG-I and MDA5, and their applications in cancer therapy. Transl. Res. 190, 51–60 (2017).

    CAS  PubMed  Google Scholar 

  130. Ranoa, D. R. E. et al. Cancer therapies activate RIG-I-like receptor pathway through endogenous non-coding RNAs. Oncotarget 7, 26496 (2016).

    PubMed  PubMed Central  Google Scholar 

  131. Burnette, B. C. et al. The efficacy of radiotherapy relies upon induction of type I interferon–dependent innate and adaptive immunity. Cancer Res. 71, 2488–2496 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Harding, S. M. et al. Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature 548, 466 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Mackenzie, K. J. et al. cGAS surveillance of micronuclei links genome instability to innate immunity. Nature 548, 461 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. de Oliveira Mann, C. C. & Kranzusch, P. J. cGAS conducts micronuclei DNA surveillance. Trends Cell Biol. 27, 697–698 (2017).

    PubMed  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  136. Rathinam, V. A. et al. The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nat. Immunol. 11, 395–402 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Shimada, K. et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity 36, 401–414 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Heid, M. E. et al. Mitochondrial reactive oxygen species induces NLRP3-dependent lysosomal damage and inflammasome activation. J. Immunol. 191, 5230–5238 (2013).

    CAS  PubMed  Google Scholar 

  139. Hu, B. et al. The DNA-sensing AIM2 inflammasome controls radiation-induced cell death and tissue injury. Science 354, 765–768 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Liu, Y. G. et al. NLRP3 inflammasome activation mediates radiation-induced pyroptosis in bone marrow-derived macrophages. Cell Death Dis. 8, e2579 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Hornung, V. et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 458, 514–518 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Guarda, G. et al. Type I interferon inhibits interleukin-1 production and inflammasome activation. Immunity 34, 213–223 (2011).

    CAS  PubMed  Google Scholar 

  143. Fernandes-Alnemri, T., Yu, J. W., Datta, P., Wu, J. & Alnemri, E. S. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 458, 509–513 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Burckstummer, T. et al. An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome. Nat. Immunol. 10, 266–272 (2009).

    PubMed  Google Scholar 

  145. Veeranki, S., Duan, X., Panchanathan, R., Liu, H. & Choubey, D. IFI16 protein mediates the anti-inflammatory actions of the type-I interferons through suppression of activation of caspase-1 by inflammasomes. PLoS ONE 6, e27040 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Henry, T., Brotcke, A., Weiss, D. S., Thompson, L. J. & Monack, D. M. Type I interferon signaling is required for activation of the inflammasome during Francisella infection. J. Exp. Med. 204, 987–994 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Gaidt, M. M. et al. The DNA inflammasome in human myeloid cells is initiated by a STING-cell death program upstream of NLRP3. Cell 171, 1110–1124. e1118 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Wang, Y. et al. Inflammasome activation triggers caspase-1-mediated cleavage of cGAS to regulate responses to DNA virus infection. Immunity 46, 393–404 (2017).

    CAS  PubMed  Google Scholar 

  149. Banerjee, I. et al. Gasdermin D restrains type I interferon response to cytosolic DNA by disrupting ionic homeostasis. Immunity 49, 413–426. e415 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Servomaa, K. & Rytömaa, T. UV light and ionizing radiations cause programmed death of rat chloroleukaemia cells by inducing retropositions of a mobile DNA element (L1Rn). Int. J. Radiat. Biol. 57, 331–343 (1990).

    CAS  PubMed  Google Scholar 

  151. Yang, W. S. et al. Regulation of ferroptotic cancer cell death by GPX4. Cell 156, 317–331 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Dixon, S. J. et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060–1072 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Lang, X. et al. Radiotherapy and immunotherapy promote tumoral lipid oxidation and ferroptosis via synergistic repression of SLC7A11. Cancer Discov. https://doi.org/10.1158/2159-8290.CD-19-0338 (2019).

    PubMed  PubMed Central  Google Scholar 

  154. Wang, W. et al. CD8(+) T cells regulate tumour ferroptosis during cancer immunotherapy. Nature 569, 270–274 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Garg, A. D. et al. Molecular and translational classifications of DAMPs in immunogenic cell death. Front. Immunol. 6, 588 (2015).

    PubMed  PubMed Central  Google Scholar 

  156. Kroemer, G., Galluzzi, L., Kepp, O. & Zitvogel, L. Immunogenic cell death in cancer therapy. Annu Rev. Immunol. 31, 51–72 (2013).

    CAS  PubMed  Google Scholar 

  157. Zhou, J. et al. Immunogenic cell death in cancer therapy: present and emerging inducers. J. Cell Mol. Med. 23, 4854–4865 (2019).

    PubMed  PubMed Central  Google Scholar 

  158. Zitvogel, L., Galluzzi, L., Smyth, M. J. & Kroemer, G. Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. Immunity 39, 74–88 (2013).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  160. 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).

    CAS  PubMed  Google Scholar 

  161. Pescovitz, M. D. Rituximab, an anti-cd20 monoclonal antibody: history and mechanism of action. Am. J. Transpl. 6, 859–866 (2006).

    CAS  Google Scholar 

  162. Baselga, J. & Albanell, J. Mechanism of action of anti-HER2 monoclonal antibodies. Ann. Oncol. 12(Suppl 1), S35–S41, https://doi.org/10.1093/annonc/12.suppl_1.s35 (2001).

    Article  PubMed  Google Scholar 

  163. Valabrega, G., Montemurro, F. & Aglietta, M. Trastuzumab: mechanism of action, resistance and future perspectives in HER2-overexpressing breast cancer. Ann. Oncol. 18, 977–984 (2007).

    CAS  PubMed  Google Scholar 

  164. Clynes, R. A., Towers, T. L., Presta, L. G. & Ravetch, J. V. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat. Med. 6, 443–446 (2000).

    CAS  PubMed  Google Scholar 

  165. Maloney, D. G. Anti-CD20 antibody therapy for B-cell lymphomas. N. Engl. J. Med. 366, 2008–2016 (2012).

    CAS  PubMed  Google Scholar 

  166. Ren, Z. et al. CTLA-4 limits anti-CD20-mediated tumor regression. Clin. Cancer Res. 23, 193–203 (2017).

    CAS  PubMed  Google Scholar 

  167. Dominguez, C., Tsang, K. Y. & Palena, C. Short-term EGFR blockade enhances immune-mediated cytotoxicity of EGFR mutant lung cancer cells: rationale for combination therapies. Cell Death Dis. 7, e2380 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Arnould, L. et al. Trastuzumab-based treatment of HER2-positive breast cancer: an antibody-dependent cellular cytotoxicity mechanism? Br. J. Cancer 94, 259–267 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Chao, M. P. et al. Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell 142, 699–713 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Stagg, J. et al. Anti-ErbB-2 mAb therapy requires type I and II interferons and synergizes with anti-PD-1 or anti-CD137 mAb therapy. Proc. Natl Acad. Sci. USA 108, 7142–7147 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Correale, P. et al. Cetuximab +/− chemotherapy enhances dendritic cell-mediated phagocytosis of colon cancer cells and ignites a highly efficient colon cancer antigen-specific cytotoxic T-cell response in vitro. Int. J. Cancer 130, 1577–1589 (2012).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  173. Liu, J. et al. Pre-clinical development of a humanized anti-CD47 antibody with anti-cancer therapeutic potential. PLoS ONE 10, e0137345 (2015).

    PubMed  PubMed Central  Google Scholar 

  174. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Liu, X. et al. CD47 blockade triggers T cell-mediated destruction of immunogenic tumors. Nat. Med. 21, 1209–1215 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Arslan, M. A., Kutuk, O. & Basaga, H. Protein kinases as drug targets in cancer. Curr. Cancer Drug Tar. 6, 623–634 (2006).

    CAS  Google Scholar 

  177. Yamaoka, T., Ohba, M. & Ohmori, T. Molecular-targeted therapies for epidermal growth factor receptor and its resistance mechanisms. Int. J. Mol. Sci .18, https://doi.org/10.3390/ijms18112420 (2017).

    PubMed Central  Google Scholar 

  178. Ciardiello, F. & Tortora, G. EGFR antagonists in cancer treatment. N. Engl. J. Med. 358, 1160–1174 (2008).

    CAS  PubMed  Google Scholar 

  179. Sequist, L. V. et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J. Clin. Oncol. 31, 3327–3334 (2013).

    CAS  PubMed  Google Scholar 

  180. Soria, J. C. et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N. Engl. J. Med. 378, 113–125 (2018).

    CAS  PubMed  Google Scholar 

  181. Xu, M., Xie, Y., Ni, S. & Liu, H. The latest therapeutic strategies after resistance to first generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in patients with non-small cell lung cancer (NSCLC). Ann. Transl. Med. 3, 96 (2015).

    PubMed  PubMed Central  Google Scholar 

  182. Stewart, E. L., Tan, S. Z., Liu, G. & Tsao, M. S. Known and putative mechanisms of resistance to EGFR targeted therapies in NSCLC patients with EGFR mutations-a review. Transl. Lung Cancer Res. 4, 67–81 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Friess, T., Scheuer, W. & Hasmann, M. Erlotinib antitumor activity in non-small cell lung cancer models is independent of HER1 and HER2 overexpression. Anticancer Res. 26, 3505–3512 (2006).

    CAS  PubMed  Google Scholar 

  184. Ioannou, N. et al. Anti-tumour activity of afatinib, an irreversible ErbB family blocker, in human pancreatic tumour cells. Br. J. Cancer 105, 1554–1562 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Cross, D. A. et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 4, 1046–1061 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Kumai, T. et al. EGFR inhibitors augment antitumour helper T-cell responses of HER family-specific immunotherapy. Br. J. Cancer 109, 2155–2166 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Yakes, F. M. et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol. Cancer Ther. 10, 2298–2308 (2011).

    CAS  PubMed  Google Scholar 

  188. Verzoni, E. et al. Potent natural killer (NK) and myeloid blood cell remodeling by cabozantinib (Cabo) in pre-treated metastatic renal cell carcinoma (mRCC) patients. Ann. Oncol. 29, https://doi.org/10.1093/annonc/mdy283.091 (2018).

  189. Lu, X. et al. Effective combinatorial immunotherapy for castration-resistant prostate cancer. Nature 543, 728–732 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Patnaik, A. et al. Efficacy and safety of abemaciclib, an inhibitor of CDK4 and CDK6, for patients with breast cancer, non-small cell lung cancer, other solid tumors. Cancer Discov. 6, 740–753 (2016).

    CAS  PubMed  Google Scholar 

  191. Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005).

    CAS  PubMed  Google Scholar 

  192. Bryant, H. E. et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913–917 (2005).

    CAS  PubMed  Google Scholar 

  193. Lord, C. J. & Ashworth, A. PARP inhibitors: Synthetic lethality in the clinic. Science 355, 1152–1158 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. Ding, L. et al. PARP inhibition elicits STING-dependent antitumor immunity in Brca1-deficient ovarian cancer. Cell Rep. 25, 2972–2980 e2975 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Pantelidou, C. et al. PARP inhibitor efficacy depends on CD8(+) T-cell recruitment via intratumoral STING pathway activation in BRCA-deficient models of triple-negative. Breast Cancer Cancer Discov. 9, 722–737 (2019).

    PubMed  Google Scholar 

  196. Choi, Y. J. et al. The requirement for cyclin D function in tumor maintenance. Cancer Cell 22, 438–451 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Sherr, C. J. & Roberts, J. M. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 13, 1501–1512 (1999).

    CAS  PubMed  Google Scholar 

  198. Goel, S. et al. CDK4/6 inhibition triggers anti-tumour immunity. Nature 548, 471 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Li, R., Bianchet, M. A., Talalay, P. & Amzel, L. M. The three-dimensional structure of NAD(P)H:quinone reductase, a flavoprotein involved in cancer chemoprotection and chemotherapy: mechanism of the two-electron reduction. Proc. Natl Acad. Sci. USA 92, 8846–8850 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Oh, E. T. et al. NQO1 inhibits proteasome-mediated degradation of HIF-1alpha. Nat. Commun. 7, 13593 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. Doskey, C. M. et al. Tumor cells have decreased ability to metabolize H2O2: implications for pharmacological ascorbate in cancer therapy. Redox Biol. 10, 274–284 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. Huang, X. M. et al. Leveraging an NQO1 bioactivatable drug for tumor-selective use of poly(ADP-ribose) polymerase inhibitors. Cancer Cell 30, 940–952 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Li, X. G. et al. NQO1 targeting prodrug triggers innate sensing to overcome checkpoint blockade resistance. Nat. Commun. 10, 3251 (2019).

  204. Sambi, M., Bagheri, L. & Szewczuk, M. R. Current challenges in cancer immunotherapy: multimodal approaches to improve efficacy and patient response rates. J. Oncol. 2019, 4508794 (2019).

    PubMed  PubMed Central  Google Scholar 

  205. Couzin-Frankel, J. Breakthrough of the year 2013. Cancer Immunother. Sci. 342, 1432–1433 (2013).

    CAS  Google Scholar 

  206. Robert, C. et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364, 2517–2526 (2011).

    CAS  PubMed  Google Scholar 

  207. Robert, C. et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372, 320–330 (2015).

    CAS  PubMed  Google Scholar 

  208. Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  209. Brahmer, J. R. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. Feins, S., Kong, W., Williams, E. F., Milone, M. C. & Fraietta, J. A. An introduction to chimeric antigen receptor (CAR) T-cell immunotherapy for human cancer. Am. J. Hematol. 94, S3–S9 (2019).

    CAS  PubMed  Google Scholar 

  211. Guo, C. et al. Therapeutic cancer vaccines: past, present, and future. Adv. Cancer Res. 119, 421–475 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. Berraondo, P. et al. Cytokines in clinical cancer immunotherapy. Br. J. Cancer 120, 6–15 (2019).

    CAS  PubMed  Google Scholar 

  213. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  214. Larkin, J., Hodi, F. S. & Wolchok, J. D. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 1270–1271 (2015).

    PubMed  Google Scholar 

  215. Herbst, R. S. et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515, 563–567 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  216. Huang, A. C. et al. T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature 545, 60–65 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. Gubin, M. M. et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 515, 577–581 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  218. Qiao, J., Liu, Z. & Fu, Y. X. Adapting conventional cancer treatment for immunotherapy. J. Mol. Med. 94, 489–495 (2016).

    CAS  PubMed  Google Scholar 

  219. Shinohara, Y. & Tsukimoto, M. Adenine nucleotides attenuate murine T cell activation induced by concanavalin A or T cell receptor stimulation. Front. Pharm. 8, 986 (2017).

    Google Scholar 

  220. la Sala, A. et al. Extracellular ATP induces a distorted maturation of dendritic cells and inhibits their capacity to initiate Th1 responses. J. Immunol. 166, 1611–1617 (2001).

    PubMed  Google Scholar 

  221. Aymeric, L. et al. Tumor cell death and ATP release prime dendritic cells and efficient anticancer immunity. Cancer Res. 70, 855–858 (2010).

    CAS  PubMed  Google Scholar 

  222. Deng, L. et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J. Clin. Investig. 124, 687–695 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  223. Muroyama, Y. et al. Stereotactic radiotherapy increases functionally suppressive regulatory T cells in the tumor microenvironment. Cancer Immunol. Res. 5, 992–1004 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  224. Liang, H. et al. Host STING-dependent MDSC mobilization drives extrinsic radiation resistance. Nat. Commun. 8, 1736 (2017).

    PubMed  PubMed Central  Google Scholar 

  225. Lee, Y. et al. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood 114, 589–595 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  226. Gupta, A. et al. Radiotherapy promotes tumor-specific effector CD8+ T cells via dendritic cell activation. J. Immunol. 189, 558–566 (2012).

    CAS  PubMed  Google Scholar 

  227. Weiss, T. et al. NKG2D-dependent antitumor effects of chemotherapy and radiotherapy against glioblastoma. Clin. Cancer Res. 24, 882–895 (2018).

    CAS  PubMed  Google Scholar 

  228. Dhar, P. & Wu, J. D. NKG2D and its ligands in cancer. Curr. Opin. Immunol. 51, 55–61 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  229. Deng, L. et al. Irradiation and anti–PD-L1 treatment synergistically promote antitumor immunity in mice. J. Clin. Investig. 124, 687–695 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  230. Dovedi, S. J. et al. Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res. 74, 5458–5468 (2014).

    CAS  PubMed  Google Scholar 

  231. Demaria, S. & Formenti, S. C. Role of T lymphocytes in tumor response to radiotherapy. Front. Oncol. 2, 95 (2012).

    PubMed  PubMed Central  Google Scholar 

  232. Filatenkov, A. et al. Ablative tumor radiation can change the tumor immune cell microenvironment to induce durable complete remissions. Clin. Cancer Res. 21, 3727–3739 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  233. Schaue, D., Kachikwu, E. L. & McBride, W. H. Cytokines in radiobiological responses: a review. Radiat. Res. 178, 505–523 (2012).

    PubMed  PubMed Central  Google Scholar 

  234. Marvel, D. & Gabrilovich, D. I. Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. J. Clin. Investig. 125, 3356–3364 (2015).

    PubMed  PubMed Central  Google Scholar 

  235. Movahedi, K. et al. Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell–suppressive activity. Blood 111, 4233–4244 (2008).

    CAS  PubMed  Google Scholar 

  236. Fridlender, Z. G. et al. Polarization of tumor-associated neutrophil phenotype by TGF-β:“N1” versus “N2” TAN. Cancer Cell 16, 183–194 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  237. Lindau, D., Gielen, P., Kroesen, M., Wesseling, P. & Adema, G. J. The immunosuppressive tumour network: myeloid‐derived suppressor cells, regulatory T cells and natural killer T cells. Immunology 138, 105–115 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  238. Dewan, M. Z. et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti–CTLA-4 antibody. Clin. Cancer Res. 15, 5379–5388 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  239. Demaria, S. et al. Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin. Cancer Res. 11, 728–734 (2005).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  241. Rodríguez-Ruiz, M. E., Vanpouille-Box, C., Melero, I., Formenti, S. C. & Demaria, S. Immunological mechanisms responsible for radiation-induced abscopal effect. Trends Immunol. 39, 644–655 (2018).

    PubMed  PubMed Central  Google Scholar 

  242. Luo, M. et al. Synergistic STING activation by PC7A nanovaccine and ionizing radiation improves cancer immunotherapy. J. Control Release 300, 154–160 (2019).

    CAS  PubMed  Google Scholar 

  243. Kwon, E. D. et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 15, 700–712 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  244. Gong, J., Le, T. Q., Massarelli, E., Hendifar, A. E. & Tuli, R. Radiation therapy and PD-1/PD-L1 blockade: the clinical development of an evolving anticancer combination. J. Immunother. Cancer 6, 46 (2018).

    PubMed  PubMed Central  Google Scholar 

  245. Sim, A. J. et al. Radiation therapy as a bridging strategy for CAR T cell therapy with axicabtagene ciloleucel in diffuse large B-cell lymphoma. Int. J. Radiat. Oncol. Biol. Phys. https://doi.org/10.1016/j.ijrobp.2019.05.065 (2019).

    PubMed  Google Scholar 

  246. Minn, I., Rowe, S. P., Pomper, M. G. & Enhancing, C. A. R. T-cell therapy through cellular imaging and radiotherapy. Lancet Oncol. 20, e443–e451 (2019).

    CAS  PubMed  Google Scholar 

  247. Newcomb, E. W. et al. Radiotherapy enhances antitumor effect of anti-CD137 therapy in a mouse Glioma model. Radiat. Res. 173, 426–432 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  248. Shi, W. & Siemann, D. W. Augmented antitumor effects of radiation therapy by 4-1BB antibody (BMS-469492) treatment. Anticancer Res. 26, 3445–3453 (2006).

    CAS  PubMed  Google Scholar 

  249. Demaria, S., Pilones, K. A., Vanpouille-Box, C., Golden, E. B. & Formenti, S. C. The optimal partnership of radiation and immunotherapy: from preclinical studies to clinical translation. Radiat. Res. 182, 170–181 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  250. Foote, J. B. et al. A STING agonist given with OX40 receptor and PD-L1 modulators primes immunity and reduces tumor growth in tolerized mice. Cancer Immunol. Res. 5, 468–479 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  251. Sivick, K. E. et al. Magnitude of therapeutic STING activation determines CD8+ T cell-mediated anti-tumor immunity. Cell Rep. 25, 3074–3085. e3075 (2018).

    CAS  PubMed  Google Scholar 

  252. Singh, V. K. et al. CBLB613: a TLR 2/6 agonist, natural lipopeptide of Mycoplasma arginini, as a novel radiation countermeasure. Radiat. Res. 177, 628–642 (2011).

    PubMed  Google Scholar 

  253. Dovedi, S. J. et al. Systemic delivery of a TLR7 agonist in combination with radiation primes durable antitumor immune responses in mouse models of lymphoma. Blood 121, 251–259 (2013).

    CAS  PubMed  Google Scholar 

  254. Roses, R. E., Xu, M., Koski, G. K. & Czerniecki, B. J. Radiation therapy and Toll-like receptor signaling: implications for the treatment of cancer. Oncogene 27, 200 (2008).

    CAS  PubMed  Google Scholar 

  255. Bryniarski, K., Szczepanik, M., Ptak, M., Zemelka, M. & Ptak, W. Influence of cyclophosphamide and its metabolic products on the activity of peritoneal macrophages in mice. Pharm. Rep. 61, 550–557 (2009).

    CAS  Google Scholar 

  256. Liu, P., Jaffar, J., Hellstrom, I. & Hellstrom, K. E. Administration of cyclophosphamide changes the immune profile of tumor-bearing mice. J. Immunother. 33, 53–59 (2010).

    PubMed  PubMed Central  Google Scholar 

  257. 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).

    CAS  PubMed  Google Scholar 

  258. 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).

    CAS  PubMed  Google Scholar 

  259. Zielinski, C., Knapp, S., Mascaux, C. & Hirsch, F. Rationale for targeting the immune system through checkpoint molecule blockade in the treatment of non-small-cell lung cancer. Ann. Oncol. 24, 1170–1179 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  260. Robert, C. et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364, 2517–2526 (2011).

    CAS  PubMed  Google Scholar 

  261. Liu, Z. et al. Coordinating antigen cytosolic delivery and danger signaling to program potent cross-priming by micelle-based nanovaccine. Cell Discov. 3, 17007 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  262. Brea, E. J. et al. Kinase regulation of human MHC class I molecule expression on cancer cells. Cancer Immunol. Res. 4, 936–947 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  263. Boni, A. et al. Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res. 70, 5213–5219 (2010).

    CAS  PubMed  Google Scholar 

  264. Ebert, P. J. R. et al. MAP kinase inhibition promotes T cell and anti-tumor activity in combination with PD-L1 checkpoint blockade. Immunity 44, 609–621 (2016).

    CAS  PubMed  Google Scholar 

  265. Callahan, M. K. et al. Paradoxical activation of T cells via augmented ERK signaling mediated by a RAF inhibitor. Cancer Immunol. Res. 2, 70–79 (2014).

    CAS  PubMed  Google Scholar 

  266. Hu-Lieskovan, S. et al. Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF(V600E) melanoma. Sci. Transl. Med. 7, 279ra241 (2015).

    Google Scholar 

  267. Lowe, D. B. et al. Dasatinib promotes the expansion of a therapeutically superior T-cell repertoire in response to dendritic cell vaccination against melanoma. Oncoimmunology 3, e27589 (2014).

    PubMed  PubMed Central  Google Scholar 

  268. Terme, M. et al. VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Res. 73, 539–549 (2013).

    CAS  PubMed  Google Scholar 

  269. Desar, I. M. et al. Sorafenib reduces the percentage of tumour infiltrating regulatory T cells in renal cell carcinoma patients. Int. J. Cancer 129, 507–512 (2011).

    CAS  PubMed  Google Scholar 

  270. Huang, H. et al. VEGF suppresses T-lymphocyte infiltration in the tumor microenvironment through inhibition of NF-kappaB-induced endothelial activation. FASEB J. 29, 227–238 (2015).

    CAS  PubMed  Google Scholar 

  271. Ahn, M. J. et al. EGFR TKI combination with immunotherapy in non-small cell lung cancer. Expert Opin. Drug Saf. 16, 465–469 (2017).

    CAS  PubMed  Google Scholar 

  272. Sun, Z. et al. A next-generation tumor-targeting IL-2 preferentially promotes tumor-infiltrating CD8(+) T-cell response and effective tumor control. Nat. Commun. 10, 3874 (2019).

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Casey Moore for helpful editing and discussions. Y.-X.F. holds the Mary Nell and Ralph B. Rogers Professorship in Immunology. This work was supported in part by Texas CPRIT grants RP180725 and RR150072 (CPRIT scholar in Cancer Research) to Y.-X.F.

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  1. Department of Pathology, UT Southwestern Medical Center, Dallas, TX, 75235, USA

    Zhida Liu, Chuanhui Han & Yang-Xin Fu

  2. Department of Immunology, UT Southwestern Medical Center, Dallas, TX, 75235, USA

    Yang-Xin Fu

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  1. Zhida Liu
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  2. Chuanhui Han
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Correspondence to Yang-Xin Fu.

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Liu, Z., Han, C. & Fu, YX. Targeting innate sensing in the tumor microenvironment to improve immunotherapy. Cell Mol Immunol 17, 13–26 (2020). https://doi.org/10.1038/s41423-019-0341-y

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