Clinical implications of T cell exhaustion for cancer immunotherapy

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...

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Bibliographic Details
Published in:Nature reviews. Clinical oncology Vol. 19; no. 12; pp. 775 - 790
Main Authors: Chow, Andrew, Perica, Karlo, Klebanoff, Christopher A, Wolchok, Jedd D
Format: Journal Article
Language:English
Published: England Nature Publishing Group 01.12.2022
Subjects:
Antigens
Cancer
Cancer immunotherapy
Chronic exposure
Clinical outcomes
Epigenetics
Humans
Immune Checkpoint Inhibitors
Immunotherapy
Immunotherapy, Adoptive
Lymphocytes
Lymphocytes T
Microenvironments
Neoplasms
Reviews
T-Lymphocytes
Tumor Microenvironment
Tumors
ISSN:1759-4774, 1759-4782, 1759-4782
Online Access:Get full text
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Summary: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.
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ISSN:1759-4774
1759-4782
1759-4782
DOI:10.1038/s41571-022-00689-z