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Combination cancer immunotherapies tailored to the tumour microenvironment

Key Points

  • Antibodies targeting programmed cell-death protein 1 (PD-1) and its ligand PD-L1 have demonstrated clinical activity in many cancer types, and will become the immunotherapeutic backbone of future cancer treatments

  • Cancers can be divided into four types based on the absence or presence of tumour-infiltrating lymphocytes and PD-L1 expression

  • Human tumours are very heterogeneous and develop clinical resistance to monotherapies; results from preclinical studies have demonstrated that efficient antitumour strategies must focus on hitting different targets concurrently

  • Key nodes to target in combination treatment include abrogating immune suppression, inducing immunogenic cancer-cell death, enhancing antigen presentation or adjuvanticity, and inducing activation and survival of immune-effector cells

  • Exome-sequencing data is currently being mined to identify the unique neoantigen profile of selected tumours from patients and guide future personalized vaccine design for use in combination treatments

  • A large proportion of patients with 'immune ignorant' tumours, who are predicted to have a poor prognosis regardless of any current intervention, will benefit from the development of novel therapies

Abstract

Evidence suggests that cancer immunotherapy will be a major part of the combination treatment plan for many patients with many cancer types in the near future. There are many types of immune processes involving different antitumour and tumour-promoting leucocytes, and tumour cells use many strategies to evade the immune response. The tumour microenvironment can help determine which immune suppressive pathways become activated to restrain antitumour immunity. This includes immune checkpoint receptors on effector T-cells and myeloid cells, and release of inhibitory cytokines and metabolites. Therapeutic approaches that target these pathways, particularly immune-checkpoint receptors, can induce durable antitumour responses in patients with advanced-stage cancers, including melanoma. Nevertheless, many patients do not have a good response to monotherapy approaches and alternative strategies are required to achieve optimal therapeutic benefit. These strategies include eliminating the bulk of tumour cells to provoke tumour-antigen release and antigen-presenting cell (APC) function, using adjuvants to enhance APC function, and using agents that enhance effector-cell activity. In this Review, we discuss the stratification of the tumour microenvironment according to tumour-infiltrating lymphocytes and PD-L1 expression in the tumour, and how this stratification enables the design of optimal combination cancer therapies tailored to target different tumour microenvironments.

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Figure 1: Four nodes to target when inducing anti-tumour immunity.

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References

  1. Sharma, P. & Allison, J. P. The future of immune checkpoint therapy. Science 348, 56–61 (2015).

    Article  CAS  PubMed  Google Scholar 

  2. Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. 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 

  5. Teng, M. W., Galon, J., Fridman, W. H. & Smyth, M. J. From mice to humans: developments in cancer immunoediting. J. Clin. Invest. 125, 338–346 (2015).

    Article  Google Scholar 

  6. Wolchok, J. D. et al. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369, 122–133 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Hammers, H. et al. Expanded cohort results from CheckMate 016: a phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma (mRCC) [abstract]. J. Clin. Oncol. 33, a4516 (2015).

    Article  Google Scholar 

  8. Melero, I. et al. Evolving synergistic combinations of targeted immunotherapies to combat cancer. Nat. Rev. Cancer 15, 457–472 (2015).

    Article  CAS  PubMed  Google Scholar 

  9. Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ngiow, S. F. et al. A threshold level of intratumour CD8+ T cell PD1 expression dictates therapeutic response to anti-PD1. Cancer Res. 75, 3800–3811 (2015).

    Article  CAS  PubMed  Google Scholar 

  11. Teng, M. W., Ngiow, S. F., Ribas, A. & Smyth, M. J. Classifying cancers based on T-cell infiltration and PD-L1. Cancer Res. 75, 2139–2145 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Taube, J. M. et al. Co-localization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci. Transl. Med. 4, 127ra37 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Taube, J. M. et al. Association of PD-1, PD-1 ligands, and other features of the tumour immune microenvironment with response to anti-PD-1 therapy. Clin. Cancer Res. 20, 5064–5074 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Gatalica, Z. et al. Programmed cell death 1 (PD-1) and its ligand (PD-L1) in common cancers and their correlation with molecular cancer type. Cancer Epidemiol. Biomarkers Prev. 23, 2965–2970 (2014).

    Article  CAS  PubMed  Google Scholar 

  15. Uno, T. et al. Eradication of established tumours in mice by a combination antibody-based therapy. Nat. Med. 12, 693–698 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. 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 

  17. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Schadendorf, D. et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J. Clin. Oncol. 33, 1889–1894 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Eroglu, Z. et al. Long term survival with cytotoxic T lymphocyte-associated antigen 4 blockade using tremelimumab. Eur. J. Cancer http://dx.doi.org/10.1016/j.ejca.2015.08.012 (2015).

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Topalian, S. L. et al. Survival, durable tumour remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J. Clin. Oncol. 32, 1020–30 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hamid, O. et al. Safety and tumour responses with lambrolizumab (anti-PD-1) in melanoma. N. Engl. J. Med. 369, 134–144 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Herbst, R. et al. A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumours [abstract]. J. Clin. Oncol. 31, a3000 (2013).

    Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Robert, C. et al. Pembrolizumab versus Ipilimumab in advanced melanoma. N. Engl. J. Med. 372, 2521–2532 (2015).

    Article  CAS  PubMed  Google Scholar 

  26. Parsa, A. T. et al. Loss of tumour suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat. Med. 13, 84–88 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. Akbay, E. A. et al. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumours. Cancer Discov. 3, 1355–1363 (2013).

    Article  CAS  PubMed  Google Scholar 

  28. Barsoum, I. B., Smallwood, C. A., Siemens, D. R. & Graham, C. H. A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells. Cancer Res. 74, 665–674 (2014).

    Article  CAS  PubMed  Google Scholar 

  29. Noman, M. Z. et al. PD-L1 is a novel direct target of HIF-1alpha, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J. Exp. Med. 211, 781–790 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Curran, M. A., Montalvo, W., Yagita, H. & Allison, J. P. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumours. Proc. Natl Acad. Sci. USA 107, 4275–4280 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Ngiow, S. F. et al. Anti-TIM3 antibody promotes T cell IFN-gamma-mediated antitumour immunity and suppresses established tumours. Cancer Res. 71, 3540–3551 (2011).

    Article  CAS  PubMed  Google Scholar 

  32. Postow, M. A. et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N. Engl. J. Med. 372, 2006–2017 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Ribas, A. Tumour immunotherapy directed at PD-1. N. Engl. J. Med. 366, 2517–2519 (2012).

    Article  CAS  PubMed  Google Scholar 

  34. Peggs, K. S., Quezada, S. A., Chambers, C. A., Korman, A. J. & Allison, J. P. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumour activity of anti-CTLA-4 antibodies. J. Exp. Med. 206, 1717–1725 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Bulliard, Y. et al. Activating Fc gamma receptors contribute to the antitumour activities of immunoregulatory receptor-targeting antibodies. J. Exp. Med. 210, 1685–1693 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Selby, M. J. et al. Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumour activity through reduction of intratumoral regulatory T cells. Cancer Immunol. Res. 1, 32–42 (2013).

    Article  CAS  PubMed  Google Scholar 

  37. Keler, T. et al. Activity and safety of CTLA-4 blockade combined with vaccines in cynomolgus macaques. J. Immunol. 171, 6251–6259 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Kavanagh, B. et al. CTLA4 blockade expands FoxP3+ regulatory and activated effector CD4+ T cells in a dose-dependent fashion. Blood 112, 1175–1183 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Romano, E. et al. Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients. Proc. Natl Acad. Sci. USA 112, 6140–6145 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ribas, A. et al. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J. Clin. Oncol. 31, 616–622 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ribas, A. Anti-CTLA4 antibody clinical trials in melanoma. Update Cancer Ther. 2, 133–139 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Duraiswamy, J., Kaluza, K. M., Freeman, G. J. & Coukos, G. Dual blockade of PD-1 and CTLA-4 combined with tumour vaccine effectively restores T cell rejection function in tumours. Cancer Res. 73, 3591–3603 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wang, W. et al. PD1 blockade reverses the suppression of melanoma antigen-specific CTL by CD4+ CD25(Hi) regulatory T cells. Int. Immunol. 21, 1065–1077 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wilson, N. S. et al. An Fcgamma receptor-dependent mechanism drives antibody-mediated target-receptor signalling in cancer cells. Cancer Cell 19, 101–113 (2011).

    Article  CAS  PubMed  Google Scholar 

  45. Li, F. & Ravetch, J. V. Antitumour activities of agonistic anti-TNFR antibodies require differential FcγRIIB coengagement in vivo. Proc. Natl Acad. Sci. USA 110, 19501–19506 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Dahan, R. et al. FcγRs modulate the anti-tumour activity of antibodies targeting the PD-1/PD-L1 axis. Cancer Cell 28, 285–295 (2015).

    Article  CAS  PubMed  Google Scholar 

  47. Nimmerjahn, F., Gordan, S. & Lux, A. FcgammaR dependent mechanisms of cytotoxic, agonistic, and neutralizing antibody activities. Trends Immunol. 36, 325–336 (2015).

    Article  CAS  PubMed  Google Scholar 

  48. Chames, P. & Baty, D. Bispecific antibodies for cancer therapy: the light at the end of the tunnel? MAbs 1, 539–547 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Schaefer, G. et al. A two-in-one antibody against HER3 and EGFR has superior inhibitory activity compared with monospecific antibodies. Cancer Cell 20, 472–486 (2011).

    Article  CAS  PubMed  Google Scholar 

  50. Kontermann, R. E. & Brinkmann, U. Bispecific antibodies. Drug Discov. Today 20, 838–847 (2015).

    Article  CAS  PubMed  Google Scholar 

  51. Nunez-Prado, N. et al. The coming of age of engineered multivalent antibodies. Drug Discov. Today 20, 588–594 (2015).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Fecher, L. A., Agarwala, S. S., Hodi, F. S. & Weber, J. S. Ipilimumab and its toxicities: a multidisciplinary approach. Oncologist 18, 733–743 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Callahan, M. K. & Wolchok, J. D. At the bedside: CTLA-4- and PD-1-blocking antibodies in cancer immunotherapy. J. Leukoc. Biol. 94, 41–53 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Marabelle, A. et al. Depleting tumour-specific Tregs at a single site eradicates disseminated tumours. J. Clin. Invest. 123, 2447–2463 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Sakuishi, K. et al. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumour immunity. J. Exp. Med. 207, 2187–2194 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Woo, S. R. et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 72, 917–927 (2012).

    Article  CAS  PubMed  Google Scholar 

  58. Fourcade, J. et al. Upregulation of Tim-3 and PD-1 expression is associated with tumour antigen-specific CD8+ T cell dysfunction in melanoma patients. J. Exp. Med. 207, 2175–2186 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Yang, Z. Z. et al. IL-12 upregulates TIM-3 expression and induces T cell exhaustion in patients with follicular B cell non-Hodgkin lymphoma. J. Clin. Invest. 122, 1271–1282 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Sakuishi, K. et al. TIM3+FOXP3+ regulatory T cells are tissue-specific promoters of T-cell dysfunction in cancer. Oncoimmunology 2, e23849 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Johnston, R. J. et al. The immunoreceptor TIGIT regulates antitumour and antiviral CD8(+) T cell effector function. Cancer Cell 26, 923–37 (2014).

    Article  CAS  PubMed  Google Scholar 

  62. Chan, C. J. et al. The receptors CD96 and CD226 oppose each other in the regulation of natural killer cell functions. Nat. Immunol. 15, 431–438 (2014).

    Article  CAS  PubMed  Google Scholar 

  63. Chauvin, J. M. et al. TIGIT and PD-1 impair tumour antigen-specific CD8(+) T cells in melanoma patients. J. Clin. Invest. 125, 2046–2058 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Sharma, P., Wagner, K., Wolchok, J. D. & Allison, J. P. Novel cancer immunotherapy agents with survival benefit: recent successes and next steps. Nat. Rev. Cancer 11, 805–812 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Melero, I. et al. Monoclonal antibodies against the 4–1BB T-cell activation molecule eradicate established tumours. Nat. Med. 3, 682–685 (1997).

    Article  CAS  PubMed  Google Scholar 

  66. Ascierto, P. A., Kalos, M., Schaer, D. A., Callahan, M. K. & Wolchok, J. D. Biomarkers for immunostimulatory monoclonal antibodies in combination strategies for melanoma and other tumour types. Clin. Cancer Res. 19, 1009–1020 (2013).

    Article  CAS  PubMed  Google Scholar 

  67. Kohrt, H. E. et al. CD137 stimulation enhances the antilymphoma activity of anti-CD20 antibodies. Blood 117, 2423–2432 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Kohrt, H. E. et al. Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer. J. Clin. Invest. 122, 1066–1075 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Mahoney, K. M., Rennert, P. D. & Freeman, G. J. Combination cancer immunotherapy and new immunomodulatory targets. Nat. Rev. Drug Discov. 14, 561–584 (2015).

    Article  CAS  PubMed  Google Scholar 

  70. Beatty, G. L. et al. CD40 agonists alter tumour stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 331, 1612–1616 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Beatty, G. L. et al. A phase I study of an agonist CD40 monoclonal antibody (CP-870,893) in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma. Clin. Cancer Res. 19, 6286–6295 (2013).

    Article  CAS  PubMed  Google Scholar 

  72. Royal, R. E. et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J. Immunother. 33, 828–833 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Ralph, C. et al. Modulation of lymphocyte regulation for cancer therapy: a phase II trial of tremelimumab in advanced gastric and esophageal adenocarcinoma. Clin. Cancer Res. 16, 1662–1672 (2010).

    Article  CAS  PubMed  Google Scholar 

  74. Kroemer, G., Galluzzi, L., Zitvogel, L. & Fridman, W. H. Colorectal cancer: the first neoplasia found to be under immunosurveillance and the last one to respond to immunotherapy? Oncoimmunology 4, e1058597 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. von Scheidt, B. et al. Combined anti-CD40 and anti-IL-23 monoclonal antibody therapy effectively suppresses tumour growth and metastases. Cancer Res. 74, 2412–2421 (2014).

    Article  CAS  PubMed  Google Scholar 

  76. Teng, M. W. et al. IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases. Nat. Med. 21, 719–729 (2015).

    Article  CAS  PubMed  Google Scholar 

  77. Young, A., Mittal, D., Stagg, J. & Smyth, M. J. Targeting cancer-derived adenosine: new therapeutic approaches. Cancer Discov. 4, 879–888 (2014).

    Article  CAS  PubMed  Google Scholar 

  78. Munn, D. H. Blocking IDO activity to enhance anti-tumour immunity. Front. Biosci. (Elite Ed.) 4, 734–745 (2012).

    Article  Google Scholar 

  79. Gabrilovich, D. I., Ostrand-Rosenberg, S. & Bronte, V. Coordinated regulation of myeloid cells by tumours. Nat. Rev. Immunol. 12, 253–268 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Mittal, D. et al. Antimetastatic effects of blocking PD-1 and the adenosine A2A receptor. Cancer Res. 74, 652–658 (2014).

    Article  CAS  Google Scholar 

  81. Ostuni, R., Kratochvill, F., Murray, P. J. & Natoli, G. Macrophages and cancer: from mechanisms to therapeutic implications. Trends Immunol. 36, 229–239 (2015).

    Article  CAS  PubMed  Google Scholar 

  82. De Palma, M. & Lewis, C. E. Macrophage regulation of tumour responses to anticancer therapies. Cancer Cell 23, 277–286 (2013).

    Article  CAS  PubMed  Google Scholar 

  83. Ruffell, B. et al. Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells. Cancer Cell 26, 623–637 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Ngiow, S. F., Teng, M. W. & Smyth, M. J. A balance of interleukin-12 and -23 in cancer. Trends Immunol. 34, 548–555 (2013).

    Article  CAS  PubMed  Google Scholar 

  85. DeNardo, D. G. et al. Leucocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov. 1, 54–67 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Pyonteck, S. M. et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat. Med. 19, 1264–72 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. De Palma, M. et al. Tie2 identifies a haematopoietic lineage of proangiogenic monocytes required for tumour vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 8, 211–226 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. Bonapace, L. et al. Cessation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis. Nature 515, 130–133 (2014).

    Article  CAS  PubMed  Google Scholar 

  89. Qian, B.-Z. et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475, 222–225 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Braghiroli, M. I., Sabbaga, J. & Hoff, P. M. Bevacizumab: overview of the literature. Expert Rev. Anticancer Ther. 12, 567–580 (2012).

    Article  CAS  PubMed  Google Scholar 

  91. Hodi, F. S. et al. Bevacizumab plus ipilimumab in patients with metastatic melanoma. Cancer Immunol. Res. 2, 632–642 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Giraldo, N. A. et al. The immune contexture of primary and metastatic human tumours. Curr. Opin. Immunol. 27, 8–15 (2014).

    Article  CAS  PubMed  Google Scholar 

  93. Pradere, J. P., Dapito, D. H. & Schwabe, R. F. The Yin and Yang of Toll-like receptors in cancer. Oncogene 33, 3485–3495 (2014).

    Article  CAS  PubMed  Google Scholar 

  94. Parmiani, G. et al. Opposite immune functions of GM-CSF administered as vaccine adjuvant in cancer patients. Ann. Oncol. 18, 226–232 (2007).

    Article  CAS  PubMed  Google Scholar 

  95. Rosenberg, S. A. IL-2: the first effective immunotherapy for human cancer. J. Immunol. 192, 5451–5458 (2014).

    Article  CAS  PubMed  Google Scholar 

  96. Zitvogel, L., Galluzzi, L., Kepp, O., Smyth, M. J. & Kroemer, G. Type I interferons in anticancer immunity. Nat. Rev. Immunol. 15, 405–414 (2015).

    Article  CAS  PubMed  Google Scholar 

  97. Teng, M. W. et al. Combined natural killer T-cell based immunotherapy eradicates established tumours in mice. Cancer Res. 67, 7495–7504 (2007).

    Article  CAS  PubMed  Google Scholar 

  98. Bald, T. et al. Immune cell-poor melanomas benefit from PD-1 blockade after targeted type I IFN activation. Cancer Discov. 4, 674–687 (2014).

    Article  CAS  PubMed  Google Scholar 

  99. Chatterjee, S. et al. TLR7 promotes tumour progression, chemotherapy resistance, and poor clinical outcomes in non-small cell lung cancer. Cancer Res. 74, 5008–5018 (2014).

    Article  CAS  PubMed  Google Scholar 

  100. Kaczanowska, S., Joseph, A. M. & Davila, E. TLR agonists: our best frenemy in cancer immunotherapy. J. Leukoc. Biol. 93, 847–863 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. McCracken, M. N., Cha, A. C. & Weissman, I. L. Molecular pathways: activating T cells after cancer cell phagocytosis from blockade of CD47 “Don't Eat Me” signals. Clin. Cancer Res. 21, 3597–3601 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Weiskopf, K. et al. Engineered SIRPα variants as immunotherapeutic adjuvants to anticancer antibodies. Science 341, 88–91 (2013).

    Article  CAS  PubMed  Google Scholar 

  103. Cioffi, M. et al. Inhibition of CD47 effectively targets pancreatic cancer stem cells via dual mechanisms. Clin. Cancer Res. 21, 2325–2337 (2015).

    Article  CAS  PubMed  Google Scholar 

  104. Kurahara, H. et al. Significance of M2-polarized tumour-associated macrophage in pancreatic cancer. J. Surg. Res. 167, e211–e219 (2011).

    Article  PubMed  Google Scholar 

  105. Feng, M. et al. Macrophages eat cancer cells using their own calreticulin as a guide: toles of TLR and Btk. Proc. Natl Acad. Sci. USA 112, 2145–2150 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  110. 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).

    Article  CAS  PubMed  Google Scholar 

  111. Weber, J. S. et al. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or naive melanoma. J. Clin. Oncol. 31, 4311–4318 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Weber, J. et al. Survival, biomarker, and toxicity analysis of nivolumab (NIVO) in patients that progressed on ipilimumab (IPI) [abstract]. J. Clin. Oncol. 33, a9055 (2015).

    Article  Google Scholar 

  113. [No authors listed] An open-label, randomized, phase 2 study of nivolumab (NIVO) given sequentially with ipilimumab (IPI) in patients with advanced melanoma (CheckMate 064) [abstract]. ESMO [online] (2015).

  114. Demaria, S. & Formenti, S. C. Radiation as an immunological adjuvant: current evidence on dose and fractionation. Front. Oncol. 2, 153 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Barker, H. E., Paget, J. T., Khan, A. A. & Harrington, K. J. The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. Nat. Rev. Cancer 15, 409–425 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Deng, L. et al. STING-dependent cytosolic DNA sensing promotes radiation-induced Type I interferon-dependent antitumour immunity in immunogenic tumours. Immunity 41, 843–852 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Klug, F. et al. Low-dose irradiation programmes macrophage differentiation to an iNOS(+)/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell 24, 589–602 (2013).

    Article  CAS  PubMed  Google Scholar 

  118. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Schaue, D. & McBride, W. H. Opportunities and challenges of radiotherapy for treating cancer. Nat. Rev. Clin. Oncol. 12, 527–40 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Formenti, S. C. & Demaria, S. Combining radiotherapy and cancer immunotherapy: a paradigm shift. J. Natl Cancer Inst. 105, 256–265 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Kalbasi, A., June, C. H., Haas, N. & Vapiwala, N. Radiation and immunotherapy: a synergistic combination. J. Clin. Invest. 123, 2756–2763 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  125. Verbrugge, I. et al. Radiotherapy increases the permissiveness of established mammary tumours to rejection by immunomodulatory antibodies. Cancer Res. 72, 3163–3174 (2012).

    Article  CAS  PubMed  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  127. Twyman-Saint Victor, C. et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520, 373–377 (2015).

    Article  CAS  PubMed  Google Scholar 

  128. Ngiow, S. F., McArthur, G. A. & Smyth, M. J. Radiotherapy complements immune checkpoint blockade. Cancer Cell 27, 437–438 (2015).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  130. Zitvogel, L., Kepp, O. & Kroemer, G. Immune parameters affecting the efficacy of chemotherapeutic regimens. Nat. Rev. Clin. Oncol. 8, 151–160 (2011).

    Article  CAS  PubMed  Google Scholar 

  131. 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 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  134. Maio, M., Di Giacomo, A. M., Robert, C. & Eggermont, A. M. Update on the role of ipilimumab in melanoma and first data on new combination therapies. Curr. Opin. Oncol. 25, 166–172 (2013).

    Article  CAS  PubMed  Google Scholar 

  135. Lynch, T. J. et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicentre phase II study. J. Clin. Oncol. 30, 2046–2054 (2012).

    Article  CAS  PubMed  Google Scholar 

  136. Ribas, A. & Wolchok, J. D. Combining cancer immunotherapy and targeted therapy. Curr. Opin. Immunol. 25, 291–296 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Loi, S., de Azambuja, E., Pugliano, L., Sotiriou, C. & Piccart, M. J. HER2-overexpressing breast cancer: time for the cure with less chemotherapy? Curr. Opin. Oncol. 23, 547–558 (2011).

    Article  CAS  PubMed  Google Scholar 

  138. Balachandran, V. P. et al. Imatinib potentiates antitumour T cell responses in gastrointestinal stromal tumour through the inhibition of Ido. Nat. Med. 17, 1094–1100 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Wilmott, J. S. et al. Selective BRAF inhibitors induce marked T-cell infiltration into human metastatic melanoma. Clin. Cancer Res. 18, 1386–1394 (2012).

    Article  CAS  PubMed  Google Scholar 

  140. Frederick, D. T. et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favourable tumour microenvironment in patients with metastatic melanoma. Clin. Cancer Res. 19, 1225–1231 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Knight, D. A. et al. Host immunity contributes to the anti-melanoma activity of BRAF inhibitors. J. Clin. Invest. 123, 1371–1381 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Schilling, B. et al. Vemurafenib reverses immunosuppression by myeloid derived suppressor cells. Int. J. Cancer 133, 1653–1663 (2013).

    Article  CAS  PubMed  Google Scholar 

  143. Lo, J. et al. Nuclear factor kappa B-mediated CD47 upregulation promotes sorafenib resistance and its blockade synergizes the effect of sorafenib in hepatocellular carcinoma in mice. Hepatology 62, 534–545 (2015).

    Article  CAS  PubMed  Google Scholar 

  144. Spranger, S., Bao, R. & Gajewski, T. F. Melanoma-intrinsic [bgr]-catenin signalling prevents anti-tumour immunity. Nature 523, 231–235 (2015).

    Article  CAS  PubMed  Google Scholar 

  145. Ventura, A. et al. Restoration of p53 function leads to tumour regression in vivo. Nature 445, 661–665 (2007).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  147. Khalili, J. S. et al. Oncogenic BRAF(V600E) promotes stromal cell-mediated immunosuppression via induction of interleukin-1 in melanoma. Clin. Cancer Res. 18, 5329–5340 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Ribas, A., Hodi, F. S., Callahan, M., Konto, C. & Wolchok, J. Hepatotoxicity with combination of vemurafenib and ipilimumab. N. Engl. J. Med. 368, 1365–1366 (2013).

    Article  CAS  PubMed  Google Scholar 

  149. Johnson, D. B. et al. Severe cutaneous and neurologic toxicity in melanoma patients during vemurafenib administration following anti-PD-1 therapy. Cancer Immunol. Res. 1, 373–377 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Su, F. et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N. Engl. J. Med. 366, 207–215 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Hogan, B. V., Peter, M. B., Shenoy, H. G., Horgan, K. & Hughes, T. A. Surgery induced immunosuppression. The Surgeon 9, 38–43 (2011).

    Article  PubMed  Google Scholar 

  152. Kwon, E. D. et al. Elimination of residual metastatic prostate cancer after surgery and adjunctive cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade immunotherapy. Proc. Natl Acad. Sci. USA 96, 15074–15079 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Loi, S. et al. CD73 promotes anthracycline resistance and poor prognosis in triple negative breast cancer. Proc. Natl Acad. Sci. USA 110, 11091–11096 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  154. Predina, J. et al. Changes in the local tumour microenvironment in recurrent cancers may explain the failure of vaccines after surgery. Proc. Natl Acad. Sci. USA 110, E415–E424 (2013).

    Article  PubMed  Google Scholar 

  155. Frohlich, M. W. Sipuleucel-T for the treatment of advanced prostate cancer. Semin. Oncol. 39, 245–252 (2012).

    Article  CAS  PubMed  Google Scholar 

  156. Rosenberg, S. A., Restifo, N. P., Yang, J. C., Morgan, R. A. & Dudley, M. E. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat. Rev. Cancer 8, 299–308 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Kershaw, M. H., Westwood, J. A. & Darcy, P. K. Gene-engineered T cells for cancer therapy. Nat. Rev. Cancer 13, 525–541 (2013).

    Article  CAS  PubMed  Google Scholar 

  158. Restifo, N. P., Dudley, M. E. & Rosenberg, S. A. Adoptive immunotherapy for cancer: harnessing the T cell response. Nat. Rev. Immunol. 12, 269–281 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Brentjens, R. J. et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci. Transl. Med. 5, 177ra38 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Grupp, S. A. et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 368, 1509–1518 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Barrett, D. M., Grupp, S. A. & June, C. H. Chimeric antigen receptor- and TCR-modified T cells enter Main Street and Wall Street. J. Immunol. 195, 755–761 (2015).

    Article  CAS  PubMed  Google Scholar 

  162. Pegram, H. J., Smith, E. L., Rafiq, S. & Brentjens, R. J. CAR therapy for haematological cancers: can success seen in the treatment of B-cell acute lymphoblastic leukemia be applied to other haematological malignancies? Immunotherapy 7, 545–561 (2015).

    Article  CAS  PubMed  Google Scholar 

  163. Angell, H. & Galon, J. From the immune contexture to the Immunoscore: the role of prognostic and predictive immune markers in cancer. Curr. Opin. Immunol. 25, 261–267 (2013).

    Article  CAS  PubMed  Google Scholar 

  164. Galon, J., Angell, H. K., Bedognetti, D. & Marincola, F. M. The continuum of cancer immunosurveillance: prognostic, predictive, and mechanistic signatures. Immunity 39, 11–26 (2013).

    Article  CAS  PubMed  Google Scholar 

  165. Mlecnik, B. et al. Biomolecular network reconstruction identifies T-cell homing factors associated with survival in colorectal cancer. Gastroenterology 138, 1429–1440 (2010).

    Article  CAS  PubMed  Google Scholar 

  166. Ignatiadis, M. et al. Gene modules and response to neoadjuvant chemotherapy in breast cancer subtypes: a pooled analysis. J. Clin. Oncol. 30, 1996–2004 (2012).

    Article  CAS  PubMed  Google Scholar 

  167. Bindea, G. et al. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity 39, 782–795 (2013).

    Article  CAS  PubMed  Google Scholar 

  168. Savage, P., Stebbing, J., Bower, M. & Crook, T. Why does cytotoxic chemotherapy cure only some cancers? Nat. Clin. Pract. Oncol. 6, 43–52 (2009).

    Article  CAS  PubMed  Google Scholar 

  169. Abadi, Y. M. et al. Host B7x promotes pulmonary metastasis of breast cancer. J. Immunol. 190, 3806–3814 (2013).

    Article  CAS  PubMed  Google Scholar 

  170. Jeon, H. et al. Structure and cancer immunotherapy of the B7 family member B7x. Cell Rep. 9, 1089–1098 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Leung, J. & Suh, W.-K. Host B7-H4 regulates antitumour T cell responses through inhibition of myeloid-derived suppressor cells in a 4T1 tumour transplantation model. J. Immunol. 190, 6651–6661 (2013).

    Article  CAS  PubMed  Google Scholar 

  172. Flies, D. B., Wang, S., Xu, H. & Chen, L. Cutting edge: a monoclonal antibody specific for the programmed death-1 homologue prevents graft-versus-host disease in mouse models. J. Immunol. 187, 1537–1541 (2011).

    Article  CAS  PubMed  Google Scholar 

  173. Wang, L. et al. VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses. J. Exp. Med. 208, 577–592 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Fourcade, J. et al. CD8+ T cells specific for tumour antigens can be rendered dysfunctional by the tumour microenvironment through upregulation of the inhibitory receptors BTLA and PD-1. Cancer Res. 72, 887–896 (2012).

    Article  CAS  PubMed  Google Scholar 

  175. Hobo, W. et al. B and T lymphocyte attenuator mediates inhibition of tumour-reactive CD8+ T cells in patients after allogeneic stem cell transplantation. J. Immunol. 189, 39–49 (2012).

    Article  CAS  PubMed  Google Scholar 

  176. Lasaro, M. O. et al. Active immunotherapy combined with blockade of a coinhibitory pathway achieves regression of large tumour masses in cancer-prone mice. Mol. Ther. 19, 1727–1736 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Derré, L. et al. BTLA mediates inhibition of human tumour-specific CD8+ T cells that can be partially reversed by vaccination. J. Clin. Invest. 120, 157–167 (2010).

    Article  CAS  PubMed  Google Scholar 

  178. Dardalhon, V. et al. Tim-3/Galectin-9 pathway: regulation of Th1 immunity through promotion of CD11b+Ly-6G+ myeloid cells. J. Immunol. 185, 1383–1392 (2010).

    Article  CAS  PubMed  Google Scholar 

  179. Guo, Z. et al. Combined TIM-3 blockade and CD137 activation affords the long-term protection in a murine model of ovarian cancer. J. Transl. Med. 11, 215 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Zhou, Q. et al. Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia. Blood 117, 4501–4510 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Jin, D. et al. CD73 on tumour cells impairs antitumour T-cell responses: a novel mechanism of tumour-induced immune suppression. Cancer Res. 70, 2245–2255 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Allard, B., Pommey, S., Smyth, M. J. & Stagg, J. Targeting CD73 enhances the anti-tumour activity of anti-PD-1 and anti-CTLA-4 mAbs. Clin. Cancer Res. 19, 5626–5635 (2013).

    Article  CAS  PubMed  Google Scholar 

  183. Beavis, P. A. et al. Blockade of A2A receptors potently suppresses the metastasis of CD73+ tumours. Proc. Natl Acad. Sci. USA 110, 14711–14716 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  184. Stagg, J. et al. CD73-deficient mice are resistant to carcinogenesis. Cancer Res. 72, 2190–2196 (2012).

    Article  CAS  PubMed  Google Scholar 

  185. Stagg, J. et al. Anti-CD73 antibody therapy inhibits breast tumour growth and metastasis. Proc. Natl Acad. Sci. USA 107, 1547–1552 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  186. Wang, L. et al. CD73 has distinct roles in nonhematopoietic and haematopoietic cells to promote tumour growth in mice. J. Clin. Invest. 121, 2371–2382 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Waickman, A. et al. Enhancement of tumour immunotherapy by deletion of the A2A adenosine receptor. Cancer Immunol. Immunother. 61, 917–926 (2012).

    Article  CAS  PubMed  Google Scholar 

  188. Hatfield, S. M. et al. Immunological mechanisms of the antitumour effects of supplemental oxygenation. Sci. Transl. Med. 7, 277ra30 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Cekic, C., Day, Y. J., Sag, D. & Linden, J. Myeloid expression of adenosine A2A receptor suppresses T and NK cell responses in the solid tumour microenvironment. Cancer Res. 74, 7250–7259 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Zhu, Y. et al. B7-H5 co-stimulates human T cells via CD28H. Nat. Commun. 4, 2043 (2013).

    Article  CAS  PubMed  Google Scholar 

  191. Zhao, R. et al. HHLA2 is a member of the B7 family and inhibits human CD4 and CD8 T-cell function. Proc. Natl Acad. Sci. USA 110, 9879–9884 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  192. Janakiram, M. et al. Expression, clinical significance, and receptor identification of the newest B7 family member HHLA2 protein. Clin. Cancer Res. 21, 2359–2366 (2015).

    Article  CAS  PubMed  Google Scholar 

  193. Brandt, C. S. et al. The B7 family member B7-H6 is a tumour cell ligand for the activating natural killer cell receptor NKp30 in humans. J. Exp. Med. 206, 1495–1503 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Zhang, T., Wu, M.-R. & Sentman, C. L. An NKp30-based chimeric antigen receptor promotes T cell effector functions and antitumour efficacy in vivo. J. Immunol. 189, 2290–2299 (2012).

    Article  CAS  PubMed  Google Scholar 

  195. Inozume, T. et al. Melanoma cells control anti-melanoma CTL responses via interaction between TIGIT and CD155 in the effector phase. J. Invest. Dermatol. http://dx.doi.org/10.1038/jid.2015.404.

  196. Kurtulus, S. et al. TIGIT predominantly regulates the immune response via regulatory T cells. J. Clin. Invest. http://dx.doi.org/10.1172/JCI81187.

  197. Corrales, L. et al. Direct activation of STING in the tumour microenvironment leads to potent and systemic tumour regression and immunity. Cell Rep. 11, 1018–1030 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Wang, Z. & Celis, E. STING activator c-di-GMP enhances the anti-tumour effects of peptide vaccines in melanoma-bearing mice. Cancer Immunol. Immunother. 64, 1057–1066 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Sjoblom, T. et al. The consensus coding sequences of human breast and colorectal cancers. Science 314, 268–274 (2006).

    Article  CAS  PubMed  Google Scholar 

  200. Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Schumacher, T. N. & Schreiber, R. D. Neoantigens in cancer immunotherapy. Science 348, 69–74 (2015).

    Article  CAS  PubMed  Google Scholar 

  202. Kreiter, S. et al. Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature 520, 692–696 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Rooney, M. S., Shukla, S. A., Wu, C. J., Getz, G. & Hacohen, N. Molecular and genetic properties of tumours associated with local immune cytolytic activity. Cell 160, 48–61 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Brown, S. D. et al. Neo-antigens predicted by tumour genome meta-analysis correlate with increased patient survival. Genome Res. 24, 743–750 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Van Allen, E. M. et al. Genomic correlates of response to CTLA4 blockade in metastatic melanoma. Science 350, 207–211 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Guidoboni, M. et al. Microsatellite instability and high content of activated cytotoxic lymphocytes identify colon cancer patients with a favourable prognosis. Am. J. Pathol. 159, 297–304 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Nosho, K. et al. Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review. J. Pathol. 222, 350–366 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  209. Le, D. T. et al. PD-1 blockade in tumours with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Matsushita, H. et al. Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature 482, 400–404 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Robbins, P. F. et al. Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumour-reactive T cells. Nat. Med. 19, 747–752 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Sznol, M. & Chen, L. Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer. Clin. Cancer Res. 19, 1021–1034 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors would like to thank Laurence Zitvogel and Michael Kershaw for helpful discussions. We apologize to all the authors whose work we were unable to cite due to reference limits. The work of M.W.L.T. is supported by a CDF1 Fellowship (1025552) and project grants (1021139 and 1059862) from the National Health and Medical Research Council of Australia (NHMRC), as well as grants from the Prostate Cancer Foundation of Australia (YI0510), and the Cancer Council of Queensland (CCQ; 1079876). The work of M.J.S. and S.F.N. is supported by a NHMRC Senior Principal Research Fellowship (1078671) and NHMRC Development Grant (1093566). The work of A.R. is supported by the National Institutes of Health (NIH) grant R35 CA197633.

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Correspondence to Michele W. L. Teng.

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M.J.S. has a scientific research agreement with Bristol–Myers Squibb and Medimmune and is a consultant to Kymab, F-star and Amgen. A.R. has consulted for Amgen, Genentech-Roche, GSK, Merck and Pierre Fabre, with honoraria paid to his institution. A.R. is on the Scientific Advisory Boards of Compugen, Flexus Bio and Kite Pharma. The other authors declare no competing interests.

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Smyth, M., Ngiow, S., Ribas, A. et al. Combination cancer immunotherapies tailored to the tumour microenvironment. Nat Rev Clin Oncol 13, 143–158 (2016). https://doi.org/10.1038/nrclinonc.2015.209

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