Single-Cell Profiling Defines Transcriptomic Signatures Specific to Tumor-Reactive versus Virus-Responsive CD4+ T Cells

We used single-cell mRNA sequencing to analyze the response of tumor-specific CD4+ tumor infiltrating lymphocytes (TILs) and draining lymph node (dLN) T cells. Computational approaches to characterize subpopulations identified TIL transcriptomic patterns strikingly distinct from acute and chronic anti-viral responses and dominated by diversity among T-bet-expressing T helper type 1 (Th1)-like cells. In contrast, the dLN response includes T follicular helper (Tfh) cells but lacks Th1 cells. We identify a type I interferon-driven signature in Th1-like TILs and show that it is found in human cancers, in which it is negatively associated with response to checkpoint therapy. Single-cell RNA sequencing of CD4+ T cells specific for a defined recombinant tumor antigen, sorted from the tumor microenvironment and draining lymph nodes.

本研究采用单细胞mRNA测序（single-cell mRNA sequencing）技术，对肿瘤特异性CD4+肿瘤浸润淋巴细胞（tumor-specific CD4+ tumor infiltrating lymphocytes, TILs）与引流淋巴结（draining lymph node, dLN）T细胞的免疫应答特征展开分析。通过计算方法表征细胞亚群，结果显示TILs的转录组特征与急性、慢性抗病毒免疫应答存在显著差异，且以表达T-bet的1型辅助T细胞（T helper type 1, Th1）样细胞的多样性为核心特征。与之相反，dLN的免疫应答中包含滤泡辅助T细胞（T follicular helper, Tfh），却未检测到Th1细胞群。本研究在Th1样TILs中鉴定出I型干扰素驱动的特征基因谱，并证实该特征谱在人类癌症组织中广泛存在，且与免疫检查点治疗的应答呈负相关。本数据集的测序对象为从肿瘤微环境及引流淋巴结中分选得到的、针对特定重组肿瘤抗原的CD4+ T细胞。