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Impact of oncogenic pathways on evasion of antitumour immune responses

Nature Reviews Cancer volume 18, pages 139–147 (2018)Cite this article

Subjects

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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Authors and Affiliations

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

    Stefani Spranger

  2. Department of Pathology, University of Chicago,

    Thomas F. Gajewski

  3. Department of Medicine, University of Chicago, Chicago, 60637, Illinois, 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.

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PowerPoint slides

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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