Abstract
Immunotherapy has been a remarkable clinical advancement in the treatment of cancer. T cells are pivotal to the efficacy of current cancer immunotherapies, including immune-checkpoint inhibitors and adoptive cell therapies. However, cancer is associated with T cell exhaustion, a hypofunctional state characterized by progressive loss of T cell effector functions and self-renewal capacity. The ‘un-exhausting’ of T cells in the tumour microenvironment is commonly regarded as a key mechanism of action for immune-checkpoint inhibitors, and T cell exhaustion is considered a pathway of resistance for cellular immunotherapies. Several elegant studies have provided important insights into the transcriptional and epigenetic programmes that govern T cell exhaustion. In this Review, we highlight recent discoveries related to the immunobiology of T cell exhaustion that offer a more nuanced perspective beyond this hypofunctional state being entirely undesirable. We review evidence that T cell exhaustion might be as much a reflection as it is the cause of poor tumour control. Furthermore, we hypothesize that, in certain contexts of chronic antigen stimulation, interruption of the exhaustion programme might impair T cell persistence. Therefore, the prioritization of interventions that mitigate the development of T cell exhaustion, including orthogonal cytoreduction therapies and novel cellular engineering strategies, might ultimately confer superior clinical outcomes and the greatest advances in cancer immunotherapy.
Key points
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T cell exhaustion is a hypofunctional T cell state that is associated with decreased efficacy of immune-checkpoint inhibitors (ICIs) and adoptive T cell therapies.
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Molecular features of T cell exhaustion are associated with tumour-reactive T cell receptor (TCR) clonotypes and can predict clinical benefit from ICIs.
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The effectiveness of ICI therapy is dependent on peripheral expansion and subsequent tumour-infiltration of precursor-exhausted CD8+ T cells.
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The T cell exhaustion programme protects CD8+ T cells from overstimulation-associated cell death; therefore, interruption of this programme might impair the persistence of tumour-reactive T cells in patients with cancer.
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Engineering optimized receptors and downstream signalling, fine-tuning transcriptional and epigenetic states, and overcoming metabolic dysfunction can mitigate T cell exhaustion (rather than interrupting this programme per se), thereby enhancing the efficacy of chimeric antigen receptor (CAR)-engineered and TCR-engineered cell therapies.
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Acknowledgements
The authors are grateful to A. Schietinger of the Memorial Sloan Kettering Cancer Center (MSKCC; New York, NY, USA) for providing valuable feedback on the manuscript. They are also grateful for manuscript editing performed by C. Wilhelm of the MSKCC. The work of A.C. is supported by a Clinical Investigator Award from US NIH National Cancer Institute (NCI; K08 CA-248723), the Stony-Wold Herbert Fund, the International Association of Lung Cancer Research (IASLC)/International Lung Cancer Foundation (ILCF), and a Society of MSKCC Grant. The work of C.A.K. is supported by the NCI (grant R37 CA259177), Cancer Research Institute (grant CRI3176), the Damon Runyon Cancer Research Foundation (grant CI-96-18) and the Parker Institute for Cancer Immunotherapy. The work of J.D.W. is supported by the NCI (grant R01 CA056821), the Ludwig Collaborative and Swim Across America Laboratory, the Emerald Foundation, the Parker Institute for Cancer Immunotherapy and a Stand Up To Cancer (SU2C)–American Cancer Society Lung Cancer Translational Research Dream Team grant (SU2C-AACR-DT17-15). The work of all authors is supported in part by a US NIH/NCI Cancer Center Support Grant to the MSKCC (P30 CA008748).
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C.A.K. has received research grant support from Kite/Gilead and Intima Bioscience, is on the scientific and/or clinical advisory boards of Achilles Therapeutics, Aleta BioTherapeutics, Bellicum Pharmaceuticals, Catamaran Bio, Obsidian Therapeutics and T-knife, and has provided consulting services for Bristol Myers Squibb, PACT Pharma and Roche/Genentech. C.A.K. is also a co-inventor on patent-licensed applications related to T cell receptors targeting public neoantigens unrelated to the current work. J.D.W. is a consultant for Amgen, Apricity, Ascentage Pharma, Astellas, AstraZeneca, Bicara Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, CellCarta, Chugai, Daiichi Sankyo, Dragonfly, Georgiamune, Idera, Imvaq, Larkspur, Maverick Therapeutics, Merck, Psioxus, Recepta, Tizona, Trishula, Sellas, Surface Oncology, Werewolf Therapeutics. J.D.W receives grant/research support from Bristol Myers Squibb and Sephora. J.D.W has equity in Apricity, Arsenal IO, Ascentage, Beigene, Imvaq, Linneaus, Georgiamune, Maverick, Tizona Pharmaceuticals and Trieza. J.D.W is a co-inventor on the following patent applications: xenogeneic (canine) DNA vaccines, myeloid-derived suppressor cell (MDSC) assay, anti-PD-1 antibody, anti-CTLA4 antibodies, anti-GITR antibodies and methods of use thereof, Newcastle disease viruses for cancer therapy, and prediction of responsiveness to treatment with immunomodulatory therapeutics and method of monitoring abscopal effects during such treatment. A.C. and K.P. declare no competing interests.
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Nature Reviews Clinical Oncology thanks A. Marabelle, who co-reviewed with A. Rubinsztajn; J. Melenhorst, who co-reviewed with Z. Zhao; I. Melero; and D. Speiser for their contribution to the peer review of this work.
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Chow, A., Perica, K., Klebanoff, C.A. et al. Clinical implications of T cell exhaustion for cancer immunotherapy. Nat Rev Clin Oncol 19, 775–790 (2022). https://doi.org/10.1038/s41571-022-00689-z
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DOI: https://doi.org/10.1038/s41571-022-00689-z
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