Key Points
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T cell dysfunction ('exhaustion') occurs in chronic infection and cancer
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Mechanisms of T cell dysfunction are partly disease specific and are partly shared between different diseases
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T cell dysfunction depends on antigens, co-stimulation, T cell inhibitory cells, metabolic pathways and soluble factors of the tumour microenvironment
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T cells are regulated by signals of the T cell receptor and co-activating, inhibitory and cytokine receptors
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T cell inhibition frequently occurs via evolutionarily conserved mechanisms known to function in most inflammatory diseases, assuring efficient downregulation of lymphocyte cytotoxicity to avoid extended tissue damage
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T cell inhibition can also occur via mechanisms that cancer cells acquired by somatic mutations
Abstract
Recent progress in cancer immunotherapy emphasizes the importance of understanding immune-regulatory pathways in tumours. Dysfunction of antitumour T cells may be due to mechanisms that are evolutionarily conserved or acquired by somatic mutations. The dysfunctional state of T cells has been termed 'exhaustion', on the basis of similarities to dysfunctional T cells in chronic infections. However, despite shared properties, recent studies have identified marked differences between T cell dysfunction in cancer and chronic infection. In this Review, we discuss T cell-intrinsic molecular alterations and metabolic communication in the tumour microenvironment. Identification of the underlying molecular drivers of T cell dysfunction is essential for the continued progress of cancer research and therapy.
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Acknowledgements
The authors acknowledge the vast and invaluable work that could not be cited here because of space limitations. The authors thank M. de Palma and T. Murray for revising the manuscript, and G. Coukos, M. Delorenzi, M. Gilliet, O. Michielin, Ch. Münz, N. Neubert, P. Romero, L. Tillé and D. Zehn and their group members for collaboration. The authors acknowledge all members of their teams and their collaborators and patients for their dedication, contributions and discussions. This work was supported in part by funds from Ludwig Cancer Research, the Cancer Research Institute, the Wilhelm Sander Foundation, the Swiss Cancer Research (3507-09-2014), the Swiss National Science Foundation (CRSII3_141879, 320030_152856), Novartis Foundation for medical-biological Research, Melanoma Research Alliance, Harry J. Lloyd Charitable Trust, SwissTransMed (KIP 18) and a grant from Alfred and Annemarie von Sick.
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Glossary
- Type 1 immune responses
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Viral or intracellular bacterial infections trigger innate immune responses accompanied by the activation of cytotoxic CD8+ T cells and CD4+ T helper 1 cells. Similar T cell populations are believed to mediate the antitumour lymphocyte effects.
- Dysfunctional T cells
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T cells in chronic infection show reduced proliferation and cytokine production because of repetitive antigen stimulation and dysbalanced co-stimulatory and inhibitory signals. T cells in cancer may show similar functional alterations in the tumour microenvironment because of similar and/or different molecular signals.
- Professional antigen-presenting cells
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(APCs). Priming and strong boosting of T cells requires professional APCs, particularly dendritic cells, which achieve this goal via the expression of co-stimulatory membrane ligands (for example, CD80 and CD86) and the secretion of cytokines (for example, interleukin-12 and interferons).
- Tumour-infiltrating T lymphocytes
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(TILs). Intratumoural T cells. In mice and humans, the main immune cell populations that can destroy cancers ('antitumour T cells') are cytotoxic CD8+ T cells and CD4+ T helper 1 (TH1) cells.
- M2-like macrophages
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A macrophage subset that is stimulated by interleukin-4 (IL-4) or IL-13 and that expresses arginase 1, the mannose receptor CD206 and the IL-4 receptor α-chain.
- M1-like macrophages
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A macrophage subset that is activated by Toll-like receptor ligands (such as lipopolysaccharide) and interferon-γ. M1-like macrophages express pro-inflammatory cytokines and inducible nitric oxide synthase, among other things.
- Anergic T cells
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T cells primed through T cell receptor (TCR) stimulation without any co-stimulation become unresponsive to further stimulation with antigen; they stop proliferating and producing cytokines.
- Senescent T cells
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T cells that have accomplished excessive numbers of divisions reach a point of irreversible cell cycle arrest.
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Speiser, D., Ho, PC. & Verdeil, G. Regulatory circuits of T cell function in cancer. Nat Rev Immunol 16, 599–611 (2016). https://doi.org/10.1038/nri.2016.80
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DOI: https://doi.org/10.1038/nri.2016.80
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