Impact of oncogenic pathways on evasion of antitumour immune responses

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Immunotherapeutic interventions are showing effectiveness across a wide range of cancer types, but only a subset of patients shows clinical response to therapy. Responsiveness to checkpoint blockade immunotherapy is favoured by the presence of a local, CD8+ T cell-based immune response within the tumour microenvironment. As molecular analyses of tumours containing or lacking a productive CD8+ T cell infiltrate are being pursued, increasing evidence is indicating that activation of oncogenic pathways in tumour cells can impair induction or execution of a local antitumour immune response. This Review summarizes our current knowledge of the influence of oncogenic effects on evasion of antitumour immunity.

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  1. 1.

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

  2. 2.

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

  3. 3.

    et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23–34 (2015).

  4. 4.

    et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357, 409–413 (2017).

  5. 5.

    et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014). This work provides proof that response to checkpoint blockade therapy (anti-PD1) is associated with the presence of T cells in the tumour microenvironment (TME) (T cell-inflamed phenotype).

  6. 6.

    , & Chemokines expressed in melanoma metastases associated with T cell infiltration. J. Clin. Oncol. 25, 8501–8501 (2007).

  7. 7.

    et al. IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J. Clin. Invest. 127, 2930–2940 (2017).

  8. 8.

    et al. Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. Cancer Res. 69, 3077–3085 (2009).

  9. 9.

    et al. Colocalization 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).

  10. 10.

    et al. An immune-active tumor microenvironment favours clinical response to ipilimumab. Cancer Immunol. Immunother. 61, 1019–1031 (2012).

  11. 11.

    et al. Density of immunogenic antigens does not explain the presence or absence of the T-cell-inflamed tumor microenvironment in melanoma. Proc. Natl Acad. Sci. USA 113, E7759–E7768 (2016).

  12. 12.

    et al. Clinical response of a patient to anti-PD-1 immunotherapy and the immune landscape of testicular germ cell tumors. Cancer Immunol. Res. 4, 903–909 (2016).

  13. 13.

    , & Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 523, 231–235 (2015). This work shows for the first time that an oncogenic signalling pathway can directly affect the local anti-tumour immune response and mediate T cell exclusion.

  14. 14.

    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).

  15. 15.

    , , , & Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell 160, 48–61 (2015).

  16. 16.

    et al. Batf3 deficiency reveals a critical role for CD8α+ dendritic cells in cytotoxic T cell immunity. Science 322, 1097–1100 (2008).

  17. 17.

    et al. Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8α+ dendritic cells. J. Exp. Med. 208, 2005–2016 (2011).

  18. 18.

    et al. Peripheral CD103+ dendritic cells form a unified subset developmentally related to CD8α+ conventional dendritic cells. J. Exp. Med. 207, 823–836 (2010).

  19. 19.

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

  20. 20.

    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).

  21. 21.

    et al. Dendritic cells but not macrophages sense tumor mitochondrial DNA for cross-priming through signal regulatory protein α signaling. Immunity 47, 363–373.e5 (2017).

  22. 22.

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

  23. 23.

    et al. Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity. Cancer Cell 26, 638–652 (2014).

  24. 24.

    et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N. Engl. J. Med. 375, 819–829 (2016).

  25. 25.

    et al. Integrated molecular analysis of tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals markers of response and resistance. Sci. Transl Med. 379, eaah3560 (2017).

  26. 26.

    et al. Non-redundant requirement for CXCR3 signalling during tumoricidal T-cell trafficking across tumour vascular checkpoints. Nat. Commun. 6, 7458 (2015).

  27. 27.

    , , & Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168, 707–723 (2017).

  28. 28.

    Mechanisms of tumor escape in the context of the T-cell-inflamed and the non-T-cell-inflamed tumor microenvironment. Int. Immunol. 28, 383–391 (2016).

  29. 29.

    et al. Association of PD-1/PD-L axis expression with cytolytic activity, mutational load, and prognosis in melanoma and other solid tumors. Proc. Natl Acad. Sci. USA 113, E7769–E7777 (2016).

  30. 30.

    et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350, 1079–1084 (2015).

  31. 31.

    et al. Heterogeneous tumor-immune microenvironments among differentially growing metastases in an ovarian cancer patient. Cell 170, 927–938.e20 (2017).

  32. 32.

    et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350, 1084–1089 (2015).

  33. 33.

    et al. in Proceedings of the American Association for Cancer Research Vol 58, abstr. 4006 (Washington, DC, 2017).

  34. 34.

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

  35. 35.

    et al. Baseline β-catenin, programmed death-ligand 1 expression and tumour-infiltrating lymphocytes predict response and poor prognosis in BRAF inhibitor-treated melanoma patients. Eur. J. Cancer 78, 70–81 (2017).

  36. 36.

    et al. BrafV600E cooperates with Pten loss to induce metastatic melanoma. Nat. Genet. 41, 544–552 (2009).

  37. 37.

    et al. Characterization of melanocyte-specific inducible Cre recombinase transgenic mice. Genesis 44, 262–267 (2006).

  38. 38.

    et al. Stabilization of β-catenin induces lesions reminiscent of prostatic intraepithelial neoplasia, but terminal squamous transdifferentiation of other secretory epithelia. Oncogene 21, 4099–4107 (2002).

  39. 39.

    et al. β-Catenin signaling controls metastasis in Braf-activated Pten-deficient melanomas. Cancer Cell 20, 741–754 (2011).

  40. 40.

    , , & Tumor-residing Batf3 dendritic cells are required for effector T cell trafficking and adoptive T cell therapy. Cancer Cell 31, 711–723.e14 (2017). This work provides a fundamental link between effector T cell recruitment into the TME and the presence of BATF3-driven DCs residing within the TME.

  41. 41.

    et al. Molecular drivers of the non-T-cell-inflamed tumor microenvironment in urothelial bladder cancer. Cancer Immunol. Res. 4, 563–568 (2016).

  42. 42.

    et al. Integrative and comparative genomic analysis of HPV-positive and HPV-negative head and neck squamous cell carcinomas. Clin. Cancer Res. 21, 632–641 (2015). This work provides indications that activation of the WNT–β-catenin pathway is associated with failed T cell infiltration in patient samples.

  43. 43.

    , , & & Correlation of WNT/β-catenin pathway activation with immune exclusion across most human cancers [abstract]. J. Clin. Oncol. 34 (Suppl.) 3004 (2016).

  44. 44.

    et al. Integrative analyses of colorectal cancer show immunoscore is a stronger predictor of patient survival than microsatellite instability. Immunity 44, 698–711 (2016).

  45. 45.

    et al. Immune and stromal classification of colorectal cancer is associated with molecular subtypes and relevant for precision immunotherapy. Clin. Cancer Res. 22, 4057–4066 (2016).

  46. 46.

    et al. The consensus molecular subtypes of colorectal cancer. Nat. Med. 21, 1350–1356 (2015).

  47. 47.

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

  48. 48.

    , 3rd, , & Targeting neoantigens to augment antitumour immunity. Nat. Rev. Cancer 17, 569 (2017).

  49. 49.

    MYC on the path to cancer. Cell 149, 22–35 (2012).

  50. 50.

    et al. Cellular senescence is an important mechanism of tumor regression upon c-Myc inactivation. Proc. Natl Acad. Sci. USA 104, 13028–13033 (2007).

  51. 51.

    , , , & MYC, metabolism, and cancer. Cancer Discov. 5, 1024–1039 (2015).

  52. 52.

    et al. Sustained loss of a neoplastic phenotype by brief inactivation of MYC. Science 297, 102–104 (2002).

  53. 53.

    et al. CD4+ T cells contribute to the remodeling of the microenvironment required for sustained tumor regression upon oncogene inactivation. Cancer Cell 18, 485–498 (2010).

  54. 54.

    , , & Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat. Rev. Cancer 16, 275–287 (2016).

  55. 55.

    et al. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell 138, 271–285 (2009).

  56. 56.

    et al. MYC regulates the antitumor immune response through CD47 and PD-L1. Science 352, 227–231 (2016).

  57. 57.

    et al. LKB1 modulates lung cancer differentiation and metastasis. Nature 448, 807–810 (2007).

  58. 58.

    et al. STK11/LKB1 deficiency promotes neutrophil recruitment and proinflammatory cytokine production to suppress T-cell activity in the lung tumor microenvironment. Cancer Res. 76, 999–1008 (2016). This preclinical mouse model provides evidence that LKB1 activation in NSCLC is associated with increased neutrophils and decreased T cell infiltration.

  59. 59.

    & The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat. Rev. Cancer 9, 563–575 (2009).

  60. 60.

    et al. Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov. 6, 202–216 (2016). This work, using clinical samples and preclinical mouse models, indicates a strong association between PTEN loss, PI3K activation and the non-T cell-inflamed phenotype.

  61. 61.

    et al. PI3K inhibition reduces mammary tumor growth and facilitates antitumor immunity and anti-PD1 responses. Clin. Cancer Res. 23, 3371–3384 (2017).

  62. 62.

    et al. Glimpse into the future: harnessing autophagy to promote anti-tumor immunity with the DRibbles vaccine. J. Immunother. Cancer 4, 25 (2016).

  63. 63.

    et al. Cross-presentation of tumor associated antigens through tumor-derived autophagosomes. Autophagy 5, 576–577 (2009).

  64. 64.

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

  65. 65.

    US National Library of Medicine. (2017).

  66. 66.

    et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656–660 (2007).

  67. 67.

    , , , & p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells. J. Exp. Med. 210, 2057–2069 (2013).

  68. 68.

    et al. Lymphocyte invasion in IC10/basal-like breast tumors is associated with wild-type TP53. Mol. Cancer Res.: MCR13, 493–501 (2015).

  69. 69.

    et al. Isocitrate dehydrogenase mutations suppress STAT1 and CD8+ T cell accumulation in gliomas. J. Clin. Invest. 127, 1425–1437 (2017).

  70. 70.

    US National Library of Medicine. (2017).

  71. 71.

    et al. Loss of IFN-γ pathway genes in tumor cells as a mechanism of resistance to anti-CTLA-4 therapy. Cell 167, 397–404.e9 (2016).

  72. 72.

    , , & STAT3 activation: a key factor in tumor immunoescape. JAKSTAT 2, e23010 (2013).

  73. 73.

    et al. Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat. Med. 10, 48–54 (2004).

  74. 74.

    et al. Stat3 activity in melanoma cells affects migration of immune effector cells and nitric oxide-mediated antitumor effects. J. Immunol. 174, 3925–3931 (2005).

  75. 75.

    et al. Enhancing chemotherapy efficacy in Pten-deficient prostate tumors by activating the senescence-associated antitumor immunity. Cell Rep. 9, 75–89 (2014).

  76. 76.

    et al. Inhibitory roles of signal transducer and activator of transcription 3 in antitumor immunity during carcinogen-induced lung tumorigenesis. Cancer Res. 72, 2990–2999 (2012).

  77. 77.

    et al. Claudin-low bladder tumors are immune infiltrated and actively immune suppressed. JCI Insight 1, e85902 (2016).

  78. 78.

    et al. Genomic activation of PPARG reveals a candidate therapeutic axis in bladder cancer. Cancer Res. (2017).

  79. 79.

    & Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression. Oncogene 25, 6817–6830 (2006).

  80. 80.

    Regulation of cell death and autophagy by IKK and NF-κB: critical mechanisms in immune function and cancer. Immunol. Rev. 246, 327–345 (2012).

  81. 81.

    et al. IKKβ links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118, 285–296 (2004).

  82. 82.

    et al. NF-κB functions as a tumour promoter in inflammation-associated cancer. Nature 431, 461–466 (2004).

  83. 83.

    et al. NF-κB hyperactivation in tumor tissues allows tumor-selective reprogramming of the chemokine microenvironment to enhance the recruitment of cytolytic T effector cells. Cancer Res. 72, 3735–3743 (2012).

  84. 84.

    et al. Requirement for NF-κB signalling in a mouse model of lung adenocarcinoma. Nature 462, 104–107 (2009).

  85. 85.

    et al. Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat. Med. 20, 607–615 (2014).

  86. 86.

    et al. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell 162, 1257–1270 (2015).

  87. 87.

    , , & The spectrum of T cell metabolism in health and disease. Nat. Rev. Immunol. (2017).

  88. 88.

    et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 527, 249–253 (2015).

  89. 89.

    et al. Expansion and activation of CD103+ dendritic cell progenitors at the tumor site enhances tumor responses to therapeutic PD-L1 and BRAF inhibition. Immunity 44, 924–938 (2016).

  90. 90.

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

  91. 91.

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

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S.S. was supported by the National Cancer Institute K99/R00CA204595 transition grant. T.F.G. was supported by R35 CA210098 and the American Cancer Society-Jules L. Plangere Jr. Family Foundation Professorship in Cancer Immunotherapy.

Author information


  1. The Koch Institute for Integrative Cancer Research at MIT and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

    • Stefani Spranger
  2. Department of Pathology, University of Chicago.

    • Thomas F. Gajewski
  3. Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.

    • Thomas F. Gajewski


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S.S. and T.F.G. researched data for the article, made substantial contributions to discussions of the content, wrote the article and reviewed and/or edited the manuscript before submission.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Stefani Spranger or Thomas F. Gajewski.


Checkpoint blockade therapy

Includes all therapies targeting immune inhibitory molecules or pathways mediating a decrease of T cell function within the tumour microenvironment. The most prominent examples are anti- cytotoxic T lymphocyte antigen 4 (CTLA4) and anti-programmed death receptor 1 (PD1) antibodies.

T cell-inflamed

A microenvironment in which CD8+ T cells are found within the tumour mass or the invasive margin of the tumour. T cells produce interferon γ (IFNγ) and other cytokines yet at the same time express immune inhibitory molecules on their surface, including programmed death receptor 1 (PD1).

Non-T cell-inflamed

A microenvironment that is representative of all tumour microenvironments with no evidence of an ongoing CD8+ T cell-driven immune response and lack of expression of key chemokines and cytokines. This group of tumours might be quite diverse.

Basic leucine zipper transcriptional factor ATF-like 3 lineage dendritic cells

(BATF3 DCs). Cells defined by the expression of the transcription factors BATF3 and interferon regulatory factor 8 (IRF8). In mice, they express lineage markers CD8α and/or CD103 (also known as ITGAE), while in humans, they express thrombomodulin (TM; also known as CD141). This lineage of DCs has the capability to cross-present tumour-derived antigens to CD8+ T cells.

Oncogenic pathways

Tumour cell-intrinsic signalling pathways with a known capability to mediate tumour induction or progression from within the tumour cells themselves. They are often but not always associated with specific mutations in oncogenes or tumour suppressor genes.