T 细胞耗竭的分子机制及其在肿瘤免疫治疗中的靶向策略

当 T 细胞持续受到抗原刺激时，它们会逐渐失去战斗能力，这种情况被称为 T 细胞衰竭。这是免疫监视和免疫疗法效果的主要障碍，并且在肿瘤环境和慢性病毒感染中经常观察到。最近的单细胞分析和谱系追踪研究显示，疲劳的 T 淋巴细胞有不同的亚群，这些亚群受 TOX、TCF-1、NR4A 等转录因子以及表观遗传修饰的调控。本文描述了 T 细胞衰竭，解释了其在转录和表观遗传水平上的调控机制，讲述了肿瘤环境如何导致这种情况，并讨论了利用免疫检查点抑制剂和新型联合策略针对 T 细胞衰竭的最新进展。逆转 T 细胞耗竭和增强抗肿瘤免疫是主要目标。

Keywords

T 细胞耗竭；免疫检查点阻断；肿瘤微环境；TOX；表观遗传调控

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References

[1]Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol. 2015;15(8):486-499.
[2]McLane LM, Abdel-Hakeem MS, Wherry EJ. CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer. Annu Rev Immunol. 2019;37:457-495.
[3]Wei SC, Duffy CR, Allison JP. Fundamental Mechanisms of Immune Checkpoint Blockade Therapy. Cancer Discov. 2018;8(9):1069-1086.
[4]Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015;27(4):450-461.
[5]Philip M, Fairchild L, Sun L, et al. Chromatin states define tumour-specific T cell dysfunction and reprogramming. Nature. 2017;545(7655):452-456.
[6]Miller BC, Sen DR, Al Abosy R, et al. Subsets of exhausted CD8⁺ T cells differentially mediate tumor control and respond to checkpoint blockade. Nat Immunol. 2019;20(3):326-336.
[7]Khan O, Giles JR, McDonald S, et al. TOX transcriptionally and epigenetically programs CD8⁺ T cell exhaustion. Nature. 2019;571(7764):211-218.
[8]Scott AC, Dündar F, Zumbo P, et al. TOX is a critical regulator of tumour-specific T cell differentiation. Nature. 2019;571(7764):270-274.
[9]Sade-Feldman M, Yizhak K, Bjorgaard SL, et al. Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma. Cell. 2018;175(4):998-1013.e20.
[10]Tirosh I, Izar B, Prakadan SM, et al. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science. 2016;352(6282):189-196.

Abstract

References

[1]Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol. 2015;15(8):486-499.

[2]McLane LM, Abdel-Hakeem MS, Wherry EJ. CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer. Annu Rev Immunol. 2019;37:457-495.

[3]Wei SC, Duffy CR, Allison JP. Fundamental Mechanisms of Immune Checkpoint Blockade Therapy. Cancer Discov. 2018;8(9):1069-1086.

[4]Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015;27(4):450-461.

[5]Philip M, Fairchild L, Sun L, et al. Chromatin states define tumour-specific T cell dysfunction and reprogramming. Nature. 2017;545(7655):452-456.

[6]Miller BC, Sen DR, Al Abosy R, et al. Subsets of exhausted CD8⁺ T cells differentially mediate tumor control and respond to checkpoint blockade. Nat Immunol. 2019;20(3):326-336.

[7]Khan O, Giles JR, McDonald S, et al. TOX transcriptionally and epigenetically programs CD8⁺ T cell exhaustion. Nature. 2019;571(7764):211-218.

[8]Scott AC, Dündar F, Zumbo P, et al. TOX is a critical regulator of tumour-specific T cell differentiation. Nature. 2019;571(7764):270-274.

[9]Sade-Feldman M, Yizhak K, Bjorgaard SL, et al. Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma. Cell. 2018;175(4):998-1013.e20.

[10]Tirosh I, Izar B, Prakadan SM, et al. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science. 2016;352(6282):189-196.