期刊
NATURE REVIEWS CLINICAL ONCOLOGY
卷 19, 期 12, 页码 775-790出版社
NATURE PORTFOLIO
DOI: 10.1038/s41571-022-00689-z
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资金
- US NIH National Cancer Institute (NCI) [K08 CA-248723]
- Stony-Wold Herbert Fund
- International Association of Lung Cancer Research (IASLC)/International Lung Cancer Foundation (ILCF)
- Society of MSKCC Grant
- NCI [R37 CA259177, R01 CA056821]
- Cancer Research Institute [CRI3176]
- Damon Runyon Cancer Research Foundation [CI-96-18]
- Parker Institute for Cancer Immunotherapy
- Ludwig Collaborative and Swim Across America Laboratory
- Emerald Foundation
- Stand Up To Cancer (SU2C)-American Cancer Society Lung Cancer Translational Research Dream Team grant [SU2C-AACR-DT17-15]
- US NIH/NCI Cancer Center Support Grant [P30 CA008748]
Immunotherapy has been a significant advancement in cancer treatment, with T cells playing a crucial role. However, cancer can lead to T cell exhaustion, a state of decreased function. Previous research focused on alleviating T cell exhaustion, but new findings suggest that it may be both a cause and reflection of poor tumor control. Therefore, interventions to mitigate T cell exhaustion development may lead to superior clinical outcomes in 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 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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