Exhaustion-associated regulatory regions in CD8+ tumor-infiltrating T cells (anti-PD-L1 vs Control IgG RNA-seq). Mus musculus

T cell exhaustion is a progressive loss of effector function and memory potential due to persistent antigen exposure, which occurs in chronic viral infections and cancer. Here we investigate the relation between gene expression and chromatin accessibility in CD8+ tumor-infiltrating lymphocytes (TIL) that recognize a model tumor antigen and have features of both activation and functional exhaustion. By filtering out accessible regions observed in bystander, non-exhausted, TIL and in acutely restimulated CD8+ T cells, we define a pattern of chromatin accessibility specific for T cell exhaustion, characterized by enrichment for consensus binding motifs for Nr4a and NFAT transcription factors. Anti-PD-L1 treatment of tumor-bearing mice results in cessation of tumor growth and partial rescue of cytokine production by the dysfunctional TIL, with only limited changes in gene expression and chromatin accessibility. Our studies provide a valuable resource for the molecular understanding of T cell exhaustion in cancer and other inflammatory settings. Overall design: RNA-seq from tumor-infiltrating CD8+ T cells in mice treated with anti-PD-L1 or Control IgG

T细胞耗竭（T cell exhaustion）是指因抗原持续暴露引发的效应功能与记忆潜能进行性丧失的病理状态，该现象常见于慢性病毒感染与肿瘤病变中。本研究聚焦于识别模式肿瘤抗原、同时兼具活化与功能耗竭特征的CD8+肿瘤浸润淋巴细胞（tumor-infiltrating lymphocytes, TIL），并探究其基因表达与染色质可及性之间的关联。通过剔除旁观者非耗竭TIL以及急性再刺激CD8+ T细胞中检测到的染色质可及区域，本研究明确了T细胞耗竭特异性的染色质可及性模式，该模式以Nr4a与NFAT转录因子的保守结合基序富集为核心特征。对荷瘤小鼠施以抗PD-L1治疗后，可实现肿瘤生长停滞，并部分恢复功能失调TIL的细胞因子产生能力，且该治疗仅对基因表达与染色质可及性造成有限改变。本研究为解析肿瘤及其他炎症情境下T细胞耗竭的分子机制提供了宝贵的研究资源。实验整体设计：采集经抗PD-L1或对照IgG处理的小鼠体内的肿瘤浸润CD8+ T细胞进行RNA测序。