Division of Signaling and Gene Expression, La Jolla Institute, La Jolla, CA 92037.
Signaling Systems Laboratory, University of California, Los Angeles, CA 90095.
Proc Natl Acad Sci U S A. 2017 Mar 28;114(13):E2776-E2785. doi: 10.1073/pnas.1620498114. Epub 2017 Mar 10.
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 the molecular understanding of T-cell exhaustion in cancer and other inflammatory settings.
T 细胞耗竭是由于持续的抗原暴露而导致效应功能和记忆潜能逐渐丧失的一种现象，这种现象发生在慢性病毒感染和癌症中。在这里，我们研究了识别模型肿瘤抗原且具有激活和功能耗竭特征的 CD8 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。通过过滤掉旁观者、未耗竭的 TIL 和急性再刺激的 CD8 T 细胞中观察到的可及区域，我们定义了一种特定于 T 细胞耗竭的染色质可及性模式，其特征是富含 Nr4a 和 NFAT 转录因子的共识结合基序。抗 PD-L1 治疗荷瘤小鼠可导致肿瘤生长停止，并部分挽救功能失调的 TIL 细胞因子的产生，而基因表达和染色质可及性只有有限的变化。我们的研究为癌症和其他炎症环境中 T 细胞耗竭的分子理解提供了有价值的资源。
