Clinical implications of T cell exhaustion for cancer immunotherapy

By A. Chow, Karlo Perica, C. Klebanoff, J. Wolchok. Nature Reviews Clinical Oncology, 2022

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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. T cells are key effectors of immunotherapies that have revolutionized the treatment of cancer; however, chronic exposure to tumour-associated antigens can result in progressive loss of T cell effector functions and self-renewal capacity, a state termed ‘T cell exhaustion’ that is believed to limit the efficacy of immunotherapy. This Review synthesizes the new immunobiological insights that present a more nuanced view beyond T cell exhaustion being entirely undesirable and indicate that this hypofunctional state might be as much a reflection as it is the cause of poor tumour control. Hence, the authors describe how, in certain contexts, interruption of this programme could impair T cell persistence and discuss interventions to mitigate the development of T cell exhaustion that might ultimately improve clinical outcomes. 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. Molecular features of T cell exhaustion are associated with tumour-reactive T cell receptor (TCR) clonotypes and can predict clinical benefit from ICIs. The effectiveness of ICI therapy is dependent on peripheral expansion and subsequent tumour-infiltration of precursor-exhausted CD8+ T cells. 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. 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. 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. Molecular features of T cell exhaustion are associated with tumour-reactive T cell receptor (TCR) clonotypes and can predict clinical benefit from ICIs. The effectiveness of ICI therapy is dependent on peripheral expansion and subsequent tumour-infiltration of precursor-exhausted CD8+ T cells. 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. 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.

Subfields: Immunology, Oncology

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