CD4 T-Cell Exhaustion: Does It Exist and What Are Its Roles in Cancer?

免疫系统 细胞毒性T细胞 免疫学 T细胞 癌症 疾病 CD8型 生物 医学 癌症研究 内科学 体外 遗传学
作者
Alexandra Miggelbrink,Joshua Jackson,Selena Lorrey,Ethan Srinivasan,Jessica Waibl Polania,Daniel Wilkinson,Peter E. Fecci
出处
期刊:Clinical Cancer Research [American Association for Cancer Research]
卷期号:27 (21): 5742-5752 被引量:143
标识
DOI:10.1158/1078-0432.ccr-21-0206
摘要

Abstract In chronic infections and in cancer, persistent antigen stimulation under suboptimal conditions can lead to the induction of T-cell exhaustion. Exhausted T cells are characterized by an increased expression of inhibitory markers and a progressive and hierarchical loss of function. Although cancer-induced exhaustion in CD8 T cells has been well-characterized and identified as a therapeutic target (i.e., via checkpoint inhibition), in-depth analyses of exhaustion in other immune cell types, including CD4 T cells, is wanting. While perhaps attributable to the contextual discovery of exhaustion amidst chronic viral infection, the lack of thorough inquiry into CD4 T-cell exhaustion is particularly surprising given their important role in orchestrating immune responses through T-helper and direct cytotoxic functions. Current work suggests that CD4 T-cell exhaustion may indeed be prevalent, and as CD4 T cells have been implicated in various disease pathologies, such exhaustion is likely to be clinically relevant. Defining phenotypic exhaustion in the various CD4 T-cell subsets and how it influences immune responses and disease severity will be crucial to understanding collective immune dysfunction in a variety of pathologies. In this review, we will discuss mechanistic and clinical evidence for CD4 T-cell exhaustion in cancer. Further insight into the derivation and manifestation of exhaustive processes in CD4 T cells could reveal novel therapeutic targets to abrogate CD4 T-cell exhaustion in cancer and induce a robust antitumor immune response.
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