Impact of oncogenic pathways on evasion of antitumour immune responses

Key Points

  • T cell infiltration into the tumour microenvironment (TME) is an important feature for the therapeutic activity of checkpoint blockade therapy.

  • While T cell activation can be influenced in multiple ways, oncogenic signalling within tumour cells has the potential to mediate T cell exclusion from the tumour microenvironment.

  • Some oncogenic pathways, such as activation of WNT–β-catenin and MYC, mediate failed T cell recruitment through failed accumulation or activation of antigen-presenting cells.

  • Within the antigen-presenting cell compartment, dendritic cells driven by the transcription factor basic leucine zipper transcriptional factor ATF-like 3 (BATF3) seem to be of critical importance for priming of tumour-specific CD8+ T cells.

  • Other oncogenic signalling pathways, such as loss of function of liver kinase B1 (LKB1) mutations, mediate recruitment of immune suppressive cell populations, which in turn mediate exclusion of T cells from the TME.

Abstract

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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Figure 1: Induction phase of a productive antitumour immune response.
Figure 2: Impact of oncogenic signalling on immune inhibitory pathways and cell populations.

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Acknowledgements

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.

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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.

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Correspondence to Stefani Spranger or Thomas F. Gajewski.

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Glossary

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.

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Spranger, S., Gajewski, T. Impact of oncogenic pathways on evasion of antitumour immune responses. Nat Rev Cancer 18, 139–147 (2018). https://doi.org/10.1038/nrc.2017.117

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