Strategies to reinvigorate exhausted CD8+ T cells in tumor microenvironment

Frontiers in Immunology

Immunology

Qin Ning¹  Fangfei Yan¹  Dong Xi¹  Qinghao Guo¹  Qianting Guan¹  Meiwen Han¹  Ming Wang¹ 

[1] Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Disease, Huazhong University of Science and Technology, Wuhan, Hubei, China;

关键词: exhausted CD8 + T cells;    tumor microenvironment;    immune checkpoint blockade;    transcription factor-based therapy;    epigenetic therapy;    metabolism-based therapy;    cytokine therapy;   

DOI  :  10.3389/fimmu.2023.1204363

 received in 2023-04-12, accepted in 2023-06-05,  发布年份 2023

来源: Frontiers

【 摘 要 】

CD8+ T cell exhaustion is a stable dysfunctional state driven by chronic antigen stimulation in the tumor microenvironment (TME). Differentiation of exhausted CD8+ T cells (CD8+ TEXs) is accompanied by extensive transcriptional, epigenetic and metabolic reprogramming. CD8+ TEXs are mainly characterized by impaired proliferative and cytotoxic capacity as well as the increased expression of multiple co-inhibitory receptors. Preclinical tumor studies and clinical cohorts have demonstrated that T cell exhaustion is firmly associated with poor clinical outcomes in a variety of cancers. More importantly, CD8+ TEXs are regarded as the main responder to immune checkpoint blockade (ICB). However, to date, a large number of cancer patients have failed to achieve durable responses after ICB. Therefore, improving CD8+ TEXs may be a breakthrough point to reverse the current dilemma of cancer immunotherapy and eliminate cancers. Strategies to reinvigorate CD8+ TEXs in TME mainly include ICB, transcription factor-based therapy, epigenetic therapy, metabolism-based therapy and cytokine therapy, which target on different aspects of exhaustion progression. Each of them has its advantages and application scope. In this review, we mainly focus on the major advances of current strategies to reinvigorate CD8+ TEXs in TME. We summarize their efficacy and mechanisms, identify the promising monotherapy and combined therapy and propose suggestions to enhance the treatment efficacy to significantly boost anti-tumor immunity and achieve better clinical outcomes.

【 授权许可】

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Copyright © 2023 Guan, Han, Guo, Yan, Wang, Ning and Xi