Prospects for combining targeted and conventional cancer therapy with immunotherapy

Key Points

  • The largely independent research fields of targeted and immune-based cancer therapies are integrating.

  • Research is focused on understanding the impact that targeted and conventional cancer therapies (chemotherapy and radiation) have on the generation of an antitumour immune response. Protective tumour immunity is thought to require innate immune stimulation, a robust cytotoxic T cell response and overcoming an immunosuppressive tumour microenvironment.

  • Insights into the effects of targeted therapies, along with conventional chemotherapy and radiation therapy, on the induction of antitumour immunity will help to advance the design of combination strategies that increase the rate of complete and durable clinical responses in patients.

  • Immune checkpoint inhibitors are emerging as a backbone of cancer therapy and are being combined in clinical trials with many targeted agents.

  • Key future challenges to developing rational combinations include continuing to understand the impact that all cancer therapeutics have on patients' immune systems, optimizing the therapeutic window of treatment through appropriate dosing and temporal sequencing, and prioritizing the rapidly growing number of combination therapy trials.

Abstract

Over the past 25 years, research in cancer therapeutics has largely focused on two distinct lines of enquiry. In one approach, efforts to understand the underlying cell-autonomous, genetic drivers of tumorigenesis have led to the development of clinically important targeted agents that result in profound, but often not durable, tumour responses in genetically defined patient populations. In the second parallel approach, exploration of the mechanisms of protective tumour immunity has provided several therapeutic strategies — most notably the 'immune checkpoint' antibodies that reverse the negative regulators of T cell function — that accomplish durable clinical responses in subsets of patients with various tumour types. The integration of these potentially complementary research fields provides new opportunities to improve cancer treatments. Targeted and immune-based therapies have already transformed the standard-of-care for several malignancies. However, additional insights into the effects of targeted therapies, along with conventional chemotherapy and radiation therapy, on the induction of antitumour immunity will help to advance the design of combination strategies that increase the rate of complete and durable clinical response in patients.

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Figure 1: Stimulation of innate immunity.
Figure 2: Modulation of T cell function.
Figure 3: Modulation of the tumour immunosuppressive microenvironment.
Figure 4: Mechanisms of immunogenic cell death.

References

  1. 1

    Saglio, G. et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N. Engl. J. Med. 362, 2251–2259 (2010).

    Article  CAS  PubMed  Google Scholar 

  2. 2

    Long, G. V. et al. Overall survival and durable responses in patients with BRAF V600-mutant metastatic melanoma receiving dabrafenib combined with trametinib. J. Clin. Oncol. 34, 871–878 (2016).

    Article  CAS  PubMed  Google Scholar 

  3. 3

    Planchard, D. et al. Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol. 17, 984–993 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Shepherd, F. A. et al. Erlotinib in previously treated non-small-cell lung cancer. N. Engl. J. Med. 353, 123–132 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Shaw, A. T. et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N. Engl. J. Med. 370, 1189–1197 (2014).

    CAS  Article  Google Scholar 

  6. 6

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Topalian, S. L., Drake, C. G. & Pardoll, D. M. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27, 450–461 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Coley, W. B. The treatment of malignant tumors by repeated inoculations of erysipelas. With a report of ten original cases. Am. J. Med. Sci. 105, 487–511 (1893).

    Article  Google Scholar 

  9. 9

    Mellman, I., Coukos, G. & Dranoff, G. Cancer immunotherapy comes of age. Nature 480, 480–489 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Chen, D. S. & Mellman, I. Oncology meets immunology: the cancer-immunity cycle. Immunity 39, 1–10 (2013).

    Article  CAS  PubMed  Google Scholar 

  11. 11

    Andtbacka, R. H. et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J. Clin. Oncol. 33, 2780–2788 (2015).

    Article  CAS  PubMed  Google Scholar 

  12. 12

    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 

  13. 13

    Fesnak, A. D., June, C. H. & Levine, B. L. Engineered T cells: the promise and challenges of cancer immunotherapy. Nat. Rev. Cancer 16, 566–581 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Gubin, M. M. & Schreiber, R. D. The odds of immunotherapy success. Science 350, 158–159 (2015).

    Article  CAS  PubMed  Google Scholar 

  15. 15

    Van Allen, E. M. et al. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 350, 207–211 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Morales, A., Eidinger, D. & Bruce, A. W. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J. Urol. 116, 180–183 (1976).

    Article  CAS  PubMed  Google Scholar 

  17. 17

    Stary, G. et al. Tumoricidal activity of TLR7/8-activated inflammatory dendritic cells. J. Exp. Med. 204, 1441–1451 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Trinchieri, G. & Santoli, D. Anti-viral activity induced by culturing lymphocytes with tumor-derived or virus-transformed cells. Enhancement of human natural killer cell activity by interferon and antagonistic inhibition of susceptibility of target cells to lysis. J. Exp. Med. 147, 1314–1333 (1978).

    Article  CAS  PubMed  Google Scholar 

  19. 19

    Lebwohl, M. et al. Imiquimod 5% cream for the treatment of actinic keratosis: results from two phase III, randomized, double-blind, parallel group, vehicle-controlled trials. J. Am. Acad. Dermatol. 50, 714–721 (2004).

    Article  PubMed  Google Scholar 

  20. 20

    Adams, S. et al. Topical TLR7 agonist imiquimod can induce immune-mediated rejection of skin metastases in patients with breast cancer. Clin. Cancer Res. 18, 6748–6757 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Dudek, A. Z. et al. First in human phase I trial of 852A, a novel systemic toll-like receptor 7 agonist, to activate innate immune responses in patients with advanced cancer. Clin. Cancer Res. 13, 7119–7125 (2007).

    Article  CAS  PubMed  Google Scholar 

  22. 22

    Northfelt, D. W. et al. A phase I dose-finding study of the novel Toll-like receptor 8 agonist VTX-2337 in adult subjects with advanced solid tumors or lymphoma. Clin. Cancer Res. 20, 3683–3691 (2014).

    Article  CAS  PubMed  Google Scholar 

  23. 23

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01294293 (2014).

  24. 24

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02180698 (2017).

  25. 25

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02668770 (2016).

  26. 26

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02556463 (2016).

  27. 27

    Ishikawa, H. & Barber, G. N. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455, 674–678 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Corrales, L. et al. Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity. Cell Rep. 11, 1018–1030 (2015). This paper demonstrates that direct activation of STING through intratumoural administration of selective agonists induces regression of established tumours in mice, generates systemic immune responses capable of rejecting distant metastases (abscopal effect) and results in an antitumour immune memory response.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02675439 (2016).

  30. 30

    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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Poeck, H. et al. 5′-triphosphate-siRNA: turning gene silencing and Rig-I activation against melanoma. Nat. Med. 14, 1256–1263 (2008).

    Article  CAS  PubMed  Google Scholar 

  32. 32

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02364986 (2016).

  33. 33

    Besch, R. et al. Proapoptotic signaling induced by RIG-I and MDA-5 results in type I interferon-independent apoptosis in human melanoma cells. J. Clin. Invest. 119, 2399–2411 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    He, W. et al. TLR4 signaling promotes immune escape of human lung cancer cells by inducing immunosuppressive cytokines and apoptosis resistance. Mol. Immunol. 44, 2850–2859 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. 35

    Dawson, M. A. & Kouzarides, T. Cancer epigenetics: from mechanism to therapy. Cell 150, 12–27 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Newbold, A., Falkenberg, K. J., Prince, M. H. & Johnstone, R. W. How do tumor cells respond to HDAC inhibition? FEBS J. 283, 4032–4046 (2016).

    Article  CAS  PubMed  Google Scholar 

  37. 37

    Zahnow, C. A. et al. Inhibitors of DNA methylation, histone deacetylation, and histone demethylation: a perfect combination for cancer therapy. Adv. Cancer Res. 130, 55–111 (2016).

    Article  CAS  PubMed  Google Scholar 

  38. 38

    Terranova-Barberio, M., Thomas, S. & Munster, P. N. Epigenetic modifiers in immunotherapy: a focus on checkpoint inhibitors. Immunotherapy 8, 705–719 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    West, A. C., Smyth, M. J. & Johnstone, R. W. The anticancer effects of HDAC inhibitors require the immune system. Oncoimmunology 3, e27414 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  40. 40

    Kim, K. et al. Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. Proc. Natl Acad. Sci. USA 111, 11774–11779 (2014).

    Article  CAS  PubMed  Google Scholar 

  41. 41

    Shen, L. & Pili, R. Class I histone deacetylase inhibition is a novel mechanism to target regulatory T cells in immunotherapy. Oncoimmunology 1, 948–950 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  42. 42

    Karpf, A. R. et al. Limited gene activation in tumor and normal epithelial cells treated with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine. Mol. Pharmacol. 65, 18–27 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. 43

    Karpf, A. R. et al. Inhibition of DNA methyltransferase stimulates the expression of signal transducer and activator of transcription 1, 2, and 3 genes in colon tumor cells. Proc. Natl Acad. Sci. USA 96, 14007–14012 (1999).

    Article  CAS  PubMed  Google Scholar 

  44. 44

    Li, H. et al. Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers. Oncotarget 5, 587–598 (2014).

    PubMed  PubMed Central  Google Scholar 

  45. 45

    Wang, L. et al. Decitabine enhances lymphocyte migration and function and synergizes with CTLA-4 blockade in a murine ovarian cancer model. Cancer Immunol. Res. 3, 1030–1041 (2015).

    Article  CAS  PubMed  Google Scholar 

  46. 46

    Chiappinelli, K. B. et al. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell 162, 974–986 (2015). This paper illustrates that, in ovarian cancer, DNMT inhibitors can upregulate hypermethylated ERVs, which activate an immune signalling response through the viral defence pathway. Additionally, in patients with melanoma treated with immune checkpoint inhibitors, a high viral defence signature is associated with durable clinical response, suggesting that DNMT inhibitors may sensitize patients to treatment with immunotherapy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Roulois, D. et al. DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts. Cell 162, 961–973 (2015). This paper demonstrates that the DNMT inhibitor azacitidine induces dsRNAs derived, in part, from ERVs that activate the mitochondrial antiviral RNA recognition pathway to produce an antitumour immune response.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Dewannieux, M. & Heidmann, T. Endogenous retroviruses: acquisition, amplification and taming of genome invaders. Curr. Opin. Virol. 3, 646–656 (2013).

    Article  CAS  PubMed  Google Scholar 

  49. 49

    Kassiotis, G. & Stoye, J. P. Immune responses to endogenous retroelements: taking the bad with the good. Nat. Rev. Immunol. 16, 207–219 (2016).

    Article  CAS  PubMed  Google Scholar 

  50. 50

    Thompson, P. J., Macfarlan, T. S. & Lorincz, M. C. Long terminal repeats: from parasitic elements to building blocks of the transcriptional regulatory repertoire. Mol. Cell 62, 766–776 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01928576 (2016).

  52. 52

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02608437 (2015).

  53. 53

    Margueron, R. & Reinberg, D. The Polycomb complex PRC2 and its mark in life. Nature 469, 343–349 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Nagarsheth, N. et al. PRC2 epigenetically silences TH1-type chemokines to suppress effector T-cell trafficking in colon cancer. Cancer Res. 76, 275–282 (2016).

    Article  CAS  PubMed  Google Scholar 

  55. 55

    Peng, D. et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 527, 249–253 (2015). This paper demonstrates that, in ovarian cancer mouse models, inhibition of EZH2 or DNMT1 reverses the repression of T H 1-type chemokines CXCL9 and CXCL10, increases T cell infiltrates into tumours and sensitizes to anti-PDL1 therapy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Kim, K. H. & Roberts, C. W. Targeting EZH2 in cancer. Nat. Med. 22, 128–134 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Epizyme (2016). Epizyme initiates collaboration on combination trial of tazemetostat and Tecentriq (atezolizumab) for treatment of non-Hodgkin lymphoma. http://amda-1rbic2.client.shareholder.com/releasedetail.cfm?ReleaseID=976750 (2016).

  58. 58

    Hon, G. C. et al. Global DNA hypomethylation coupled to repressive chromatin domain formation and gene silencing in breast cancer. Genome Res. 22, 246–258 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Shi, Y. et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941–953 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Harris, W. J. et al. The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer Cell 21, 473–487 (2012).

    Article  CAS  PubMed  Google Scholar 

  61. 61

    Schenk, T. et al. Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nat. Med. 18, 605–611 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Huse, M. The T-cell-receptor signaling network. J. Cell Sci. 122, 1269–1273 (2009).

    Article  CAS  PubMed  Google Scholar 

  63. 63

    DeSilva, D. R. et al. Inhibition of mitogen-activated protein kinase kinase blocks T cell proliferation but does not induce or prevent anergy. J. Immunol. 160, 4175–4181 (1998).

    CAS  PubMed  Google Scholar 

  64. 64

    D'Souza, W. N., Chang, C. F., Fischer, A. M., Li, M. & Hedrick, S. M. The Erk2 MAPK regulates CD8 T cell proliferation and survival. J. Immunol. 181, 7617–7629 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Su, B., Cheng, J., Yang, J. & Guo, Z. MEKK2 is required for T-cell receptor signals in JNK activation and interleukin-2 gene expression. J. Biol. Chem. 276, 14784–14790 (2001).

    Article  CAS  PubMed  Google Scholar 

  66. 66

    Liu, L. et al. The BRAF and MEK inhibitors dabrafenib and trametinib: effects on immune function and in combination with immunomodulatory antibodies targeting PD-1, PD-L1, and CTLA-4. Clin. Cancer Res. 21, 1639–1651 (2015).

    Article  CAS  PubMed  Google Scholar 

  67. 67

    Ebert, P. J. et al. MAP kinase inhibition promotes T cell and anti-tumor activity in combination with PD-L1 checkpoint blockade. Immunity 44, 609–621 (2016). This paper demonstrates that, although inhibition of MEK blocks naive CD8+ T cell priming in the lymph node, in the TME, MEK inhibition increases antigen-specific CD8+ T cells, protects TILs from death and combines with anti-PDL1 therapy to generate durable tumour regression in mouse models.

    Article  CAS  PubMed  Google Scholar 

  68. 68

    Bendell, J. C. et al. Clinical activity and safety of cobimetinib (cobi) and atezolizumab in colorectal cancer (CRC). J. Clin. Oncol. 34, abstr. 3502 (2016).

    Article  Google Scholar 

  69. 69

    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). This letter outlines hepatic adverse events in a clinical study evaluating the concurrent use of the BRAF inhibitor vemurafenib and the CTLA4 inhibitor ipilimumab, highlighting the dosing and sequencing challenges of combining targeted and immune-based therapies.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Gamper, C. J. & Powell, J. D. All PI3Kinase signaling is not mTOR: dissecting mTOR-dependent and independent signaling pathways in T cells. Front. Immunol. 3, 312 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Pollizzi, K. N. & Powell, J. D. Regulation of T cells by mTOR: the known knowns and the known unknowns. Trends Immunol. 36, 13–20 (2015).

    Article  CAS  Google Scholar 

  72. 72

    Peng, W. et al. Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov. 6, 202–216 (2016).

    Article  CAS  Google Scholar 

  73. 73

    Patton, D. T. et al. Cutting edge: the phosphoinositide 3-kinase p110 delta is critical for the function of CD4+CD25+Foxp3+ regulatory T cells. J. Immunol. 177, 6598–6602 (2006).

    Article  CAS  PubMed  Google Scholar 

  74. 74

    Patton, D. T., Wilson, M. D., Rowan, W. C., Soond, D. R. & Okkenhaug, K. The PI3K p110δ regulates expression of CD38 on regulatory T cells. PLoS ONE 6, e17359 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Liu, D. et al. The p110δ isoform of phosphatidylinositol 3-kinase controls susceptibility to Leishmania major by regulating expansion and tissue homing of regulatory T cells. J. Immunol. 183, 1921–1933 (2009).

    Article  CAS  PubMed  Google Scholar 

  76. 76

    Ali, K. et al. Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer. Nature 510, 407–411 (2014). This paper demonstrates that inactivation of p110δ, the catalytic subunit of PI3Kδ, in T reg cells inhibits their suppressive function and stimulates CD8+ cytotoxic T cells to induce tumour regression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02332980 (2016).

  78. 78

    Furman, R. R. et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 370, 997–1007 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Gopal, A. K. et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N. Engl. J. Med. 370, 1008–1018 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Araki, K., Ellebedy, A. H. & Ahmed, R. TOR in the immune system. Curr. Opin. Cell Biol. 23, 707–715 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Araki, K. et al. mTOR regulates memory CD8 T-cell differentiation. Nature 460, 108–112 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Wang, Y., Wang, X. Y., Subjeck, J. R., Shrikant, P. A. & Kim, H. L. Temsirolimus, an mTOR inhibitor, enhances anti-tumour effects of heat shock protein cancer vaccines. Br. J. Cancer 104, 643–652 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Jiang, Q. et al. mTOR kinase inhibitor AZD8055 enhances the immunotherapeutic activity of an agonist CD40 antibody in cancer treatment. Cancer Res. 71, 4074–4084 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Procaccini, C. et al. An oscillatory switch in mTOR kinase activity sets regulatory T cell responsiveness. Immunity 33, 929–941 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Wang, Y. et al. Regulatory T cells require mammalian target of rapamycin signaling to maintain both homeostasis and alloantigen-driven proliferation in lymphocyte-replete mice. J. Immunol. 186, 2809–2818 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Mannick, J. B. et al. mTOR inhibition improves immune function in the elderly. Sci. Transl Med. 6, 268ra179 (2014).

    Article  CAS  PubMed  Google Scholar 

  87. 87

    Fesik, S. W. Promoting apoptosis as a strategy for cancer drug discovery. Nat. Rev. Cancer 5, 876–885 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. 88

    Dougan, M. et al. IAP inhibitors enhance co-stimulation to promote tumor immunity. J. Exp. Med. 207, 2195–2206 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Varfolomeev, E. & Vucic, D. (Un)expected roles of c-IAPs in apoptotic and NFκB signaling pathways. Cell Cycle 7, 1511–1521 (2008).

    Article  CAS  PubMed  Google Scholar 

  90. 90

    Knights, A. J., Fucikova, J., Pasam, A., Koernig, S. & Cebon, J. Inhibitor of apoptosis protein (IAP) antagonists demonstrate divergent immunomodulatory properties in human immune subsets with implications for combination therapy. Cancer Immunol. Immunother. 62, 321–335 (2013).

    Article  CAS  PubMed  Google Scholar 

  91. 91

    Gentle, I. E. et al. Inhibitors of apoptosis proteins (IAPs) are required for effective T-cell expansion/survival during antiviral immunity in mice. Blood 123, 659–668 (2014).

    Article  CAS  PubMed  Google Scholar 

  92. 92

    Horwood, N. J., Urbaniak, A. M. & Danks, L. Tec family kinases in inflammation and disease. Int. Rev. Immunol. 31, 87–103 (2012).

    Article  CAS  PubMed  Google Scholar 

  93. 93

    Thomas, J. D. et al. Colocalization of X-linked agammaglobulinemia and X-linked immunodeficiency genes. Science 261, 355–358 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Kil, L. P. et al. Btk levels set the threshold for B-cell activation and negative selection of autoreactive B cells in mice. Blood 119, 3744–3756 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Hendriks, R. W., Yuvaraj, S. & Kil, L. P. Targeting Bruton's tyrosine kinase in B cell malignancies. Nat. Rev. Cancer 14, 219–232 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Dubovsky, J. A. et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood 122, 2539–2549 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Liao, X. C. & Littman, D. R. Altered T cell receptor signaling and disrupted T cell development in mice lacking Itk. Immunity 3, 757–769 (1995).

    Article  CAS  PubMed  Google Scholar 

  98. 98

    Andreotti, A. H., Schwartzberg, P. L., Joseph, R. E. & Berg, L. J. T-Cell signaling regulated by the Tec family kinase, Itk. Cold Spring Harb. Perspect. Biol. 2, a002287 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Fowell, D. J. et al. Impaired NFATc translocation and failure of Th2 development in Itk-deficient CD4+ T cells. Immunity 11, 399–409 (1999).

    Article  CAS  PubMed  Google Scholar 

  100. 100

    Sagiv-Barfi, I. et al. Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK. Proc. Natl Acad. Sci. USA 112, E966–E972 (2015). This paper demonstrates that ibrutinib, an inhibitor of the TEC family members BTK and ITK, in combination with PDL1 inhibition suppresses tumour growth in mouse models of lymphoma that are insensitive to ibrutinib alone and in solid tumours. These data suggest that this combination can be used clinically in tumours other than lymphoma.

    Article  CAS  PubMed  Google Scholar 

  101. 101

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/nCT02420912 (2016).

  102. 102

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02401048 (2016).

  103. 103

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02329847 (2016).

  104. 104

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02733042 (2016).

  105. 105

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02403271 (2017).

  106. 106

    Ruefli-Brasse, A. A., French, D. M. & Dixit, V. M. Regulation of NF-κB-dependent lymphocyte activation and development by paracaspase. Science 302, 1581–1584 (2003).

    Article  CAS  PubMed  Google Scholar 

  107. 107

    Ruland, J. et al. Bcl10 is a positive regulator of antigen receptor-induced activation of NF-κB and neural tube closure. Cell 104, 33–42 (2001).

    Article  CAS  PubMed  Google Scholar 

  108. 108

    Ruland, J., Duncan, G. S., Wakeham, A. & Mak, T. W. Differential requirement for Malt1 in T and B cell antigen receptor signaling. Immunity 19, 749–758 (2003).

    Article  CAS  PubMed  Google Scholar 

  109. 109

    Hosokawa, Y., Suzuki, H., Nakagawa, M., Lee, T. H. & Seto, M. API2-MALT1 fusion protein induces transcriptional activation of the API2 gene through NF-kappaB binding elements: evidence for a positive feed-back loop pathway resulting in unremitting NF-κB activation. Biochem. Biophys. Res. Commun. 334, 51–60 (2005).

    Article  CAS  PubMed  Google Scholar 

  110. 110

    Dierlamm, J. et al. The apoptosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;q21) associated with mucosa-associated lymphoid tissue lymphomas. Blood 93, 3601–3609 (1999).

    CAS  PubMed  Google Scholar 

  111. 111

    Dierlamm, J. et al. Gain of chromosome region 18q21 including the MALT1 gene is associated with the activated B-cell-like gene expression subtype and increased BCL2 gene dosage and protein expression in diffuse large B-cell lymphoma. Haematologica 93, 688–696 (2008).

    Article  CAS  PubMed  Google Scholar 

  112. 112

    Hailfinger, S. et al. Essential role of MALT1 protease activity in activated B cell-like diffuse large B-cell lymphoma. Proc. Natl Acad. Sci. USA 106, 19946–19951 (2009).

    Article  PubMed  Google Scholar 

  113. 113

    Ngo, V. N. et al. A loss-of-function RNA interference screen for molecular targets in cancer. Nature 441, 106–110 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    Rebeaud, F. et al. The proteolytic activity of the paracaspase MALT1 is key in T cell activation. Nat. Immunol. 9, 272–281 (2008).

    Article  CAS  PubMed  Google Scholar 

  115. 115

    Jeltsch, K. M. et al. Cleavage of roquin and regnase-1 by the paracaspase MALT1 releases their cooperatively repressed targets to promote TH17 differentiation. Nat. Immunol. 15, 1079–1089 (2014).

    Article  CAS  PubMed  Google Scholar 

  116. 116

    Klein, T. et al. The paracaspase MALT1 cleaves HOIL1 reducing linear ubiquitination by LUBAC to dampen lymphocyte NF-κB signalling. Nat. Commun. 6, 8777 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Uehata, T. et al. Malt1-induced cleavage of regnase-1 in CD4+ helper T cells regulates immune activation. Cell 153, 1036–1049 (2013).

    Article  CAS  PubMed  Google Scholar 

  118. 118

    Coornaert, B. et al. T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-κB inhibitor A20. Nat. Immunol. 9, 263–271 (2008).

    Article  CAS  PubMed  Google Scholar 

  119. 119

    Bailey, S. R. et al. Th17 cells in cancer: the ultimate identity crisis. Front. Immunol. 5, 276 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Meininger, I. et al. Alternative splicing of MALT1 controls signalling and activation of CD4+ T cells. Nat. Commun. 7, 11292 (2016). This paper outlines the mechanism by which TCR-induced alternative splicing of MALT1 enhances signalling and optimal T cell activation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Fontan, L. et al. MALT1 small molecule inhibitors specifically suppress ABC-DLBCL in vitro and in vivo. Cancer Cell 22, 812–824 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Nagel, D. et al. Pharmacologic inhibition of MALT1 protease by phenothiazines as a therapeutic approach for the treatment of aggressive ABC-DLBCL. Cancer Cell 22, 825–837 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

    Mc Guire, C. et al. Paracaspase MALT1 deficiency protects mice from autoimmune-mediated demyelination. J. Immunol. 190, 2896–2903 (2013).

    Article  CAS  PubMed  Google Scholar 

  124. 124

    Jaworski, M. et al. Malt1 protease inactivation efficiently dampens immune responses but causes spontaneous autoimmunity. EMBO J. 33, 2765–2781 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. 125

    Yu, J. W. et al. MALT1 protease activity is required for innate and adaptive immune responses. PLoS ONE 10, e0127083 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. 126

    Bornancin, F. et al. Deficiency of MALT1 paracaspase activity results in unbalanced regulatory and effector T and B cell responses leading to multiorgan inflammation. J. Immunol. 194, 3723–3734 (2015).

    Article  CAS  PubMed  Google Scholar 

  127. 127

    McKinnon, M. L. et al. Combined immunodeficiency associated with homozygous MALT1 mutations. J. Allergy Clin. Immunol. 133, 1458–1462.e7 (2014).

    Article  CAS  PubMed  Google Scholar 

  128. 128

    Punwani, D. et al. Combined immunodeficiency due to MALT1 mutations, treated by hematopoietic cell transplantation. J. Clin. Immunol. 35, 135–146 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. 129

    Turley, S. J., Cremasco, V. & Astarita, J. L. Immunological hallmarks of stromal cells in the tumour microenvironment. Nat. Rev. Immunol. 15, 669–682 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    Hugo, W. et al. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell 165, 35–44 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. 131

    Joyce, J. A. & Pollard, J. W. Microenvironmental regulation of metastasis. Nat. Rev. Cancer 9, 239–252 (2009).

    Article  CAS  PubMed  Google Scholar 

  132. 132

    Polyak, K., Haviv, I. & Campbell, I. G. Co-evolution of tumor cells and their microenvironment. Trends Genet. 25, 30–38 (2009).

    Article  CAS  PubMed  Google Scholar 

  133. 133

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. 134

    Castermans, K. & Griffioen, A. W. Tumor blood vessels, a difficult hurdle for infiltrating leukocytes. Biochim. Biophys. Acta 1776, 160–174 (2007).

    CAS  PubMed  Google Scholar 

  135. 135

    Padera, T. P. et al. Pathology: cancer cells compress intratumour vessels. Nature 427, 695 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. 136

    Jain, R. K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58–62 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Chang, C. H. et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162, 1229–1241 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. 138

    Antonioli, L., Blandizzi, C., Pacher, P. & Hasko, G. Immunity, inflammation and cancer: a leading role for adenosine. Nat. Rev. Cancer 13, 842–857 (2013).

    Article  CAS  PubMed  Google Scholar 

  139. 139

    Fredholm, B. B. et al. International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol. Rev. 53, 527–552 (2001).

    CAS  PubMed  Google Scholar 

  140. 140

    Ohta, A. et al. The development and immunosuppressive functions of CD4+ CD25+ FoxP3+ regulatory T cells are under influence of the adenosine-A2A adenosine receptor pathway. Front. Immunol. 3, 190 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. 141

    Sitkovsky, M. & Ohta, A. Targeting the hypoxia-adenosinergic signaling pathway to improve the adoptive immunotherapy of cancer. J. Mol. Med. (Berl.) 91, 147–155 (2013).

    Article  CAS  Google Scholar 

  142. 142

    Iannone, R., Miele, L., Maiolino, P., Pinto, A. & Morello, S. Adenosine limits the therapeutic effectiveness of anti-CTLA4 mAb in a mouse melanoma model. Am. J. Cancer Res. 4, 172–181 (2014).

    PubMed  PubMed Central  Google Scholar 

  143. 143

    Mittal, D. et al. Antimetastatic effects of blocking PD-1 and the adenosine A2A receptor. Cancer Res. 74, 3652–3658 (2014).

    Article  CAS  PubMed  Google Scholar 

  144. 144

    Beavis, P. A. et al. Adenosine receptor 2A blockade increases the efficacy of anti-PD-1 through enhanced antitumor T-cell responses. Cancer Immunol. Res. 3, 506–517 (2015). This paper demonstrates that CD73, a 5′-nucleoside that generates immunosuppressive adenosine in the TME, limits the efficacy of PD1 blockade. The combination of PD1 inhibition and an A2AR inhibitor increases the expression of IFNγ and granzyme B by tumor-infiltrating CD8+ T cells and significantly reduces tumour growth.

    Article  CAS  PubMed  Google Scholar 

  145. 145

    Cekic, C. & Linden, J. Adenosine A2A receptors intrinsically regulate CD8+ T cells in the tumor microenvironment. Cancer Res. 74, 7239–7249 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. 146

    Ohta, A. A. Metabolic immune checkpoint: adenosine in tumor microenvironment. Front. Immunol. 7, 109 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. 147

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02740985 (2017).

  148. 148

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02655822 (2016).

  149. 149

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02403193 (2016).

  150. 150

    Mellor, A. L. & Munn, D. H. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat. Rev. Immunol. 4, 762–774 (2004).

    Article  CAS  Google Scholar 

  151. 151

    Okamoto, A. et al. Indoleamine 2,3-dioxygenase serves as a marker of poor prognosis in gene expression profiles of serous ovarian cancer cells. Clin. Cancer Res. 11, 6030–6039 (2005).

    Article  CAS  PubMed  Google Scholar 

  152. 152

    Spranger, S. et al. Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8+ T cells directly within the tumor microenvironment. J. Immunother. Cancer 2, 3 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  153. 153

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. 154

    Ruffell, B. & Coussens, L. M. Macrophages and therapeutic resistance in cancer. Cancer Cell 27, 462–472 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. 155

    Shabo, I., Stal, O., Olsson, H., Dore, S. & Svanvik, J. Breast cancer expression of CD163, a macrophage scavenger receptor, is related to early distant recurrence and reduced patient survival. Int. J. Cancer 123, 780–786 (2008).

    Article  CAS  PubMed  Google Scholar 

  156. 156

    Komohara, Y., Ohnishi, K., Kuratsu, J. & Takeya, M. Possible involvement of the M2 anti-inflammatory macrophage phenotype in growth of human gliomas. J. Pathol. 216, 15–24 (2008).

    Article  CAS  PubMed  Google Scholar 

  157. 157

    Holmgaard, R. B., Zamarin, D., Munn, D. H., Wolchok, J. D. & Allison, J. P. Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. J. Exp. Med. 210, 1389–1402 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. 158

    Pyonteck, S. M. et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat. Med. 19, 1264–1272 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. 159

    Ries, C. H. et al. Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell 25, 846–859 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. 160

    Mao, Y. et al. Targeting suppressive myeloid cells potentiates checkpoint inhibitors to control spontaneous neuroblastoma. Clin. Cancer Res. http://dx.doi.org/10.1158/1078-0432.CCR-15-1912 (2016).

  161. 161

    Quail, D. F. et al. The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas. Science 352, aad3018 (2016). This paper demonstrates that, in a mouse model of gliobastoma, acquired resistance to M-CSFR inhibition is associated with elevated PI3K activity driven by macrophage-derived IGF1. Resistance can be overcome by combining M-CSFR inhibitors with IGF1R or PI3K blockade.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. 162

    Pienta, K. J. et al. Phase 2 study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 (CCL2), in metastatic castration-resistant prostate cancer. Invest. New Drugs 31, 760–768 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. 163

    Sandhu, S. K. et al. A first-in-human, first-in-class, phase I study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 in patients with solid tumors. Cancer Chemother. Pharmacol. 71, 1041–1050 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. 164

    Brana, I. et al. Carlumab, an anti-C-C chemokine ligand 2 monoclonal antibody, in combination with four chemotherapy regimens for the treatment of patients with solid tumors: an open-label, multicenter phase 1b study. Target. Oncol. 10, 111–123 (2015).

    Article  PubMed  Google Scholar 

  165. 165

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. 166

    Kaneda, M. M. et al. PI3Kγ is a molecular switch that controls immune suppression. Nature 539, 437–442 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. 167

    De Henau, O. et al. Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells. Nature 539, 443–447 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. 168

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02637531 (2016).

  169. 169

    Batchelor, T. T. et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11, 83–95 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. 170

    Carmeliet, P. & Jain, R. K. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat. Rev. Drug Discov. 10, 417–427 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. 171

    Willett, C. G. et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat. Med. 10, 145–147 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. 172

    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).

    Article  CAS  PubMed  Google Scholar 

  173. 173

    Guislain, A. et al. Sunitinib pretreatment improves tumor-infiltrating lymphocyte expansion by reduction in intratumoral content of myeloid-derived suppressor cells in human renal cell carcinoma. Cancer Immunol. Immunother. 64, 1241–1250 (2015).

    Article  CAS  PubMed  Google Scholar 

  174. 174

    Osada, T. et al. The effect of anti-VEGF therapy on immature myeloid cell and dendritic cells in cancer patients. Cancer Immunol. Immunother. 57, 1115–1124 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. 175

    Rini, B. I. et al. Combination immunotherapy with prostatic acid phosphatase pulsed antigen-presenting cells (provenge) plus bevacizumab in patients with serologic progression of prostate cancer after definitive local therapy. Cancer 107, 67–74 (2006).

    Article  CAS  PubMed  Google Scholar 

  176. 176

    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 

  177. 177

    Amin, A. et al. Nivolumab (anti-PD-1; BMS-936558, ONO-4538) in combination with sunitinb or pazopanib in patients (pts) with metastatic renal cell carcinoma (mRCC). J. Clin. Oncol. 32, abstr. 5010 (2014).

    Article  Google Scholar 

  178. 178

    Sznol, M. et al. Phase Ib evaluation of MPDL3280A (anti-PDL1) in combination with bevacizumab (bev) in patients (pts) with metastatic renal cell carcinoma (mRCC). J. Clin. Oncol. 33, abstr. 410 (2015).

    Article  Google Scholar 

  179. 179

    Bendell, J. C. et al. Safety and efficacy of MPDL328OA (anti-PDL1) in combination with bevacizumab (bev) and/or FOLFOX in patients (pts) with metastatic colorectal cancer (mCRC). J. Clin. Oncol. 33, abstr. 704 (2015).

    Article  Google Scholar 

  180. 180

    Wakefield, L. M. & Hill, C. S. Beyond TGFβ: roles of other TGFβ superfamily members in cancer. Nat. Rev. Cancer 13, 328–341 (2013).

    Article  CAS  PubMed  Google Scholar 

  181. 181

    Yang, L., Pang, Y. & Moses, H. L. TGF-β and immune cells: an important regulatory axis in the tumor microenvironment and progression. Trends Immunol. 31, 220–227 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. 182

    Akhurst, R. J. & Hata, A. Targeting the TGFβ signalling pathway in disease. Nat. Rev. Drug Discov. 11, 790–811 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. 183

    Wojtowicz-Praga, S. Reversal of tumor-induced immunosuppression by TGF-β inhibitors. Invest. New Drugs 21, 21–32 (2003).

    Article  CAS  PubMed  Google Scholar 

  184. 184

    Morris, J. C. et al. Phase I study of GC1008 (fresolimumab): a human anti-transforming growth factor-β (TGFβ) monoclonal antibody in patients with advanced malignant melanoma or renal cell carcinoma. PLoS ONE 9, e90353 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. 185

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02581787 (2016).

  186. 186

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02423343 (2016).

  187. 187

    Liska, D., Chen, C. T., Bachleitner-Hofmann, T., Christensen, J. G. & Weiser, M. R. HGF rescues colorectal cancer cells from EGFR inhibition via MET activation. Clin. Cancer Res. 17, 472–482 (2011).

    Article  CAS  PubMed  Google Scholar 

  188. 188

    Rutella, S. et al. Hepatocyte growth factor favors monocyte differentiation into regulatory interleukin (IL)-10++IL-12low/neg accessory cells with dendritic-cell features. Blood 108, 218–227 (2006).

    Article  CAS  PubMed  Google Scholar 

  189. 189

    Giannoni, P. et al. Chronic lymphocytic leukemia nurse-like cells express hepatocyte growth factor receptor (c-MET) and indoleamine 2,3-dioxygenase and display features of immunosuppressive type 2 skewed macrophages. Haematologica 99, 1078–1087 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. 190

    Damsky, W. E. et al. Beta-catenin signaling controls metastasis in Braf-activated Pten-deficient melanomas. Cancer Cell 20, 741–754 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. 191

    Holtzhausen, A. et al. Melanoma-derived Wnt5a promotes local dendritic-cell expression of IDO and immunotolerance: opportunities for pharmacologic enhancement of immunotherapy. Cancer Immunol. Res. 3, 1082–1095 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. 192

    Spranger, S., Bao, R. & Gajewski, T. F. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 523, 231–235 (2015). This paper demonstrates an association between activation of the WNT–β-catenin signalling pathway and the lack of a T cell gene expression signature in human samples of metastatic melanoma. Using mouse tumour models, the authors illustrate a mechanism by which tumour cell-autonomous active β-catenin signalling blocks TILs, promoting resistance to anti-PDL1 and anti-CTLA4 therapy.

    Article  CAS  Google Scholar 

  193. 193

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02649530 (2016).

  194. 194

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. 195

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. 196

    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, multicenter phase II study. J. Clin. Oncol. 30, 2046–2054 (2012).

    Article  CAS  Google Scholar 

  197. 197

    Reck, M. et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial. Ann. Oncol. 24, 75–83 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. 198

    Shalapour, S. et al. Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy. Nature 521, 94–98 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. 199

    Reck, M. et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N. Engl. J. Med. 375, 1823–1833 (2016). This paper demonstrates that in previously untreated patients with advanced NSCLC and expression of PDL1 on at least 50% of their tumour cells, PD1 blockade was associated with a significant improvement in efficacy and reduced adverse events relative to standard-of-care chemotherapy.

    Article  CAS  PubMed  Google Scholar 

  200. 200

    Langer, C. J. et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 17, 1497–1508 (2016).

    Article  CAS  PubMed  Google Scholar 

  201. 201

    Bernstein, M. B., Krishnan, S., Hodge, J. W. & Chang, J. Y. Immunotherapy and stereotactic ablative radiotherapy (ISABR): a curative approach? Nat. Rev. Clin. Oncol. 13, 516–524 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. 202

    Golden, E. B., Demaria, S., Schiff, P. B., Chachoua, A. & Formenti, S. C. An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer Immunol. Res. 1, 365–372 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  203. 203

    Hiniker, S. M. et al. A systemic complete response of metastatic melanoma to local radiation and immunotherapy. Transl Oncol. 5, 404–407 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  204. 204

    Postow, M. A. et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N. Engl. J. Med. 366, 925–931 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. 205

    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  PubMed Central  Google Scholar 

  206. 206

    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 

  207. 207

    Frederick, D. T. et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin. Cancer Res. 19, 1225–1231 (2013). This paper examines biopsies from patients with metastatic melanoma treated with a BRAF inhibitor (vemurafenib) either alone or in combination with a MEK inhibitor (dabrafenib plus trametinib) and demonstrates that either treatment results in increased expression of melanoma antigens, increased CD8+ T cell infiltrate and a decrease in immunosuppressive cytokines, consistent with a more favourable antitumour immune environment.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. 208

    Hu-Lieskovan, S. et al. Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF(V600E) melanoma. Sci. Transl Med. 7, 279ra41 (2015). This paper reports that the triple combination of BRAF, MEK and PD1 inhibition demonstrates superior antitumour efficacy in a mouse model of BRAF-V600E-driven melanoma, supporting the use of this therapeutic combination in the clinic.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. 209

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02254772 (2016).

  210. 210

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02680184 (2016).

  211. 211

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02619253 (2017).

  212. 212

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02437136 (2016).

  213. 213

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02453620 (2017).

  214. 214

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02816021 (2017).

  215. 215

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02546986 (2016).

  216. 216

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02508870 (2017).

  217. 217

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02224781 (2017).

  218. 218

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02130466 (2017).

  219. 219

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02027961 (2017).

  220. 220

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT01656642 (2016).

  221. 221

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02818023 (2017).

  222. 222

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02607813 (2017).

  223. 223

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02587962 (2016).

  224. 224

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02752074 (2017).

  225. 225

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02298153 (2016).

  226. 226

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02073123 (2016).

  227. 227

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02471846 (2017).

  228. 228

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02807844 (2017).

  229. 229

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02323191 (2016).

  230. 230

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02452424 (2016).

  231. 231

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02829723 (2017).

  232. 232

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT00790010 (2017).

  233. 233

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02210117 (2017).

  234. 234

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02337491 (2016).

  235. 235

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02420821 (2016).

  236. 236

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02795429 (2016).

  237. 237

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/show/NCT02323126 (2017).

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Correspondence to Glenn Dranoff.

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All authors are employees and shareholders of Novartis.

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Glossary

Immune checkpoint inhibitors

Therapeutic agents that reverse, for example, programmed cell death protein 1 (PD1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA4)-mediated repression of cytotoxic T cell activity to enable an antitumour immune response.

Innate immune responses

Refers to the nonspecific immune defence mechanisms that identify and eliminate foreign pathogens. Cells of the innate immune response include natural killer cells, mast cells, eosinophils, basophils and phagocytic cells such as macrophages.

Dendritic cells

(DCs). Immune cells that process and display antigenic proteins in conjunction with major histocompatibility complex proteins on their surface to T cells and are the most potent antigen-presenting cells, regulating both protective immunity and tolerance.

Natural killer (NK) cells

Immune cells that can bind to and kill virally infected cells or tumour cells in the absence of antigen stimulation.

Tumour-immunity cycle

Refers to the sequence of events — tumour-associated antigen loading and activation of dendritic cells (DCs), antigen presentation by DCs to CD8+ T cells and T cell-directed cytolysis of tumours — that are required to drive a potent antitumour response.

Type I interferon

A class of secreted proteins that induce cell-intrinsic antiviral pathways, modulate the innate immune response to promote antigen presentation and natural killer cell function and promote the development of antigen-specific (adaptive) T and B cell memory responses.

Myeloid-derived suppressor cells

(MDSCs). A heterogeneous population of cells of the myeloid lineage that can potently suppress T effector cell responses and function.

T regulatory (Treg) cells

A subpopulation of T cells that help to maintain tolerance by suppressing the induction, proliferation and activity of T effector cells.

Actinic keratosis

Refers to a rough or scaly skin lesion typically associated with sun exposure.

Endogenous retroviruses

(ERVs). Genomic viral elements that are derived from or resemble exogenous retroviruses. ERVs have been implicated in some cancers and autoimmune diseases.

T cell exhaustion

A state of T cell dysfunction characterized by diminished effector functions and sustained expression of inhibitory receptors that is associated with chronic infection and cancer.

Humoral immunity

The component of the adaptive immune response that is driven by B cell activation (with the help of CD4+ T cells), which results in the secretion of antibodies from plasma cells. It also broadly refers to secreted or soluble factors that are part of an immune response, including complement.

X-linked agammaglobulinaemia

A heritable immunodeficiency caused by a mutation in Bruton tyrosine kinase (BTK) in which patients do not generate mature B cells and hence do not make antibodies.

Waldenström macroglobulinaemia

A type of non-Hodgkin lymphoma characterized by lymphoplasmacytoid cells that secrete large amounts of monoclonal antibodies known as macroglobulin.

TH1 cells

(T helper 1 cells). An effector population of activated, differentiated CD4+ T cells characterized by the secretion of inflammatory cytokines interferon-γ and tumour necrosis factor, as well as interleukin-2.

TH17 cell

(T helper 17 cell). A type of activated CD4+ T cell that promotes neutrophil activation, immunity to pathogens and inflammation.

Immunogenic cell death

(ICD). A form of cell death that is characterized by the release of damage-associated molecular patterns (DAMPs) and results in an immunostimulatory response.

Damage-associated molecular patterns

(DAMPs). Refers to host-derived molecules such as calreticulin, high mobility group box 1 protein (HMGB1), heat shock proteins, ATP and DNA that initiate and maintain an inflammatory response.

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Gotwals, P., Cameron, S., Cipolletta, D. et al. Prospects for combining targeted and conventional cancer therapy with immunotherapy. Nat Rev Cancer 17, 286–301 (2017). https://doi.org/10.1038/nrc.2017.17

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