谱系追踪揭示了克隆祖细胞和免疫检查点阻滞治疗期间肿瘤特异性T细胞的长期持久性。
Lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade.
发表日期：2023 Mar 24
作者：
Joy A Pai, Matthew D Hellmann, Jennifer L Sauter, Marissa Mattar, Hira Rizvi, Hyung Jun Woo, Nisargbhai Shah, Evelyn M Nguyen, Fathema Z Uddin, Alvaro Quintanal-Villalonga, Joseph M Chan, Parvathy Manoj, Viola Allaj, Marina K Baine, Umesh K Bhanot, Mala Jain, Irina Linkov, Fanli Meng, David Brown, Jamie E Chaft, Andrew J Plodkowski, Mathieu Gigoux, Helen H Won, Triparna Sen, Daniel K Wells, Mark T A Donoghue, Elisa de Stanchina, Jedd D Wolchok, Brian Loomis, Taha Merghoub, Charles M Rudin, Andrew Chow, Ansuman T Satpathy
来源：
CANCER CELL
摘要：
配对的单细胞RNA和T细胞受体测序（scRNA/TCR-seq）已经增强了癌症中克隆T细胞动态的分辨率。本文报道了三个非小细胞肺癌患者在免疫检查点阻断（ICB）后，187,650个T细胞来自31个组织区域的scRNA/TCR-seq分析，包括肿瘤、相邻的正常组织和淋巴结（LN）。有活力的癌细胞区域富含疲惫的CD8+ T细胞、调节性CD4+ T细胞（Treg）和滤泡辅助CD4+ T细胞（TFH）。跨组织跟踪T细胞克隆型，结合新抗原特异性分析，揭示了TFH和特异性疲惫的CD8+ T细胞与肿瘤引流LN中的TCF7+SELL+祖细胞有克隆关联，以及CD8+ T、Treg和TFH细胞在肿瘤微环境附近的渐进性疲劳轨迹。最后，对肿瘤特异性CD8+和CD4+ T细胞克隆的纵向跟踪揭示了ICB治疗后多年在外周血液中的持续存在。版权所有©2023 Elsevier Inc.
Paired single-cell RNA and T cell receptor sequencing (scRNA/TCR-seq) has allowed for enhanced resolution of clonal T cell dynamics in cancer. Here, we report a scRNA/TCR-seq analysis of 187,650 T cells from 31 tissue regions, including tumor, adjacent normal tissues, and lymph nodes (LN), from three patients with non-small cell lung cancer after immune checkpoint blockade (ICB). Regions with viable cancer cells are enriched for exhausted CD8+ T cells, regulatory CD4+ T cells (Treg), and follicular helper CD4+ T cells (TFH). Tracking T cell clonotypes across tissues, combined with neoantigen specificity assays, reveals that TFH and tumor-specific exhausted CD8+ T cells are clonally linked to TCF7+SELL+ progenitors in tumor draining LNs, and progressive exhaustion trajectories of CD8+ T, Treg, and TFH cells with proximity to the tumor microenvironment. Finally, longitudinal tracking of tumor-specific CD8+ and CD4+ T cell clones reveals persistence in the peripheral blood for years after ICB therapy.Copyright © 2023 Elsevier Inc. All rights reserved.