Exhaustion-associated regulatory regions in CD8+ tumor-infiltrating T cells
Exhaustion-associated regulatory regions in CD8+ tumor-infiltrating T cells
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DOI：
10.1073/pnas.1620498114
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发表时间：
2017-03-28
影响因子：
11.1
通讯作者：
Trifari, Sara
中科院分区：
文献类型：
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作者：
Mognol, Giuliana P.;Spreafico, Roberto;Trifari, Sara
T细胞耗竭是由于持续的抗原暴露而导致的效应器功能和记忆潜力的进行性丧失，其发生在慢性病毒感染和癌症中。在此，我们研究了CD 8（+）肿瘤浸润淋巴细胞（TIL）中基因表达和染色质可及性之间的关系，这些TIL识别模型肿瘤抗原，具有激活和功能衰竭的特征。通过过滤掉在旁观者、未耗竭的TIL和急性再刺激的CD 8（+）T细胞中观察到的可接近区域，我们定义了一种特异于T细胞耗竭的染色质可接近性模式，其特征是Nr 4a和NFAT转录因子的共有结合基序富集。荷瘤小鼠的抗PD-L1治疗导致肿瘤生长停止和功能失调的TIL的细胞因子产生的部分拯救，基因表达和染色质可及性仅发生有限的变化。我们的研究为从分子水平理解癌症和其他炎症环境中T细胞耗竭提供了宝贵的资源。
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 (TILs) that recognize a model tumor antigen and have features of both activation and functional exhaustion. By filtering out accessible regions observed in bystander, nonexhausted TILs 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 TILs, with only limited changes in gene expression and chromatin accessibility. Our studies provide a valuable resource for themolecular understanding of T-cell exhaustion in cancer and other inflammatory settings.