Contribution of resident and circulating precursors to tumor-infiltrating CD8+ T cell populations in lung cancer [scTCR-seq]. Contribution of resident and circulating precursors to tumor-infiltrating CD8+ T cell populations in lung cancer [scTCR-seq]

Purpose: The goal of this study is to delineate the processes of CD8+ T cell differentiation in primary NSCLC by integrating transcriptomic and tcr profiles. Methods: A combination of single cell RNA and TCR sequencing (scRNA-seq and scTCR- seq) was used, in tumors, normal tissues adjacent to the tumor (juxta-tumor), and circulating blood derived from 11 patients with untreated, primary NSCLC. Results: We show that precursor, memory-like CD8+ TILs include 2 main populations: one is also present in the blood (circulating precursors); the other is also present in juxta-tumor tissue and bears markers of memory resident T cells (resident precursors). Both precursor subtypes differentiate into a main population of terminal effectors through a similar “transitional” stage. Terminal effectors are not observed in blood or juxta-tumor tissue, are more clonally expanded, and express signatures of exhaustion. A significant proportion of transitional and terminal effectors also express cell cycle signatures and Ki67, suggesting that clonal expansion occurs in situ is part of the terminal differentiation process. Overall design: 6 patients with early-stage, untreated NSCLC

研究目的：本研究旨在整合转录组与T细胞受体（TCR）谱，阐明原发性非小细胞肺癌（NSCLC）中CD8+ T细胞的分化进程。
研究方法：本研究采用单细胞RNA测序与TCR测序（scRNA-seq与scTCR-seq）联合分析方案，对11例初治原发性非小细胞肺癌患者的肿瘤组织、瘤旁（juxta-tumor）组织及外周血样本开展检测。
研究结果：本研究结果显示，前体记忆样CD8+肿瘤浸润淋巴细胞（TILs）包含两个主要亚群：其一与外周血中存在的循环前体细胞表型一致；其二存在于瘤旁组织中，具备组织驻留记忆T细胞的标志物，可称为驻留前体细胞。两类前体亚群均通过相似的“过渡态”阶段，分化为核心的终末效应细胞群。终末效应细胞未在外周血与瘤旁组织中被检出，其克隆扩增程度更高，且表达免疫耗竭特征基因集。进一步分析发现，相当比例的过渡态与终末效应细胞同时表达细胞周期特征基因与Ki67，提示原位克隆扩增是终末分化进程的重要组成部分。
整体实验设计：纳入6例早期初治非小细胞肺癌患者。