Pan-cancer T cell atlas links a cellular stress response state to immunotherapy resistance
Authors listYanshuo Chu Enyu Dai Yating Li Guangchun Han Guangsheng Pei Davis R Ingram Krupa Thakkar Jiang-Jiang Qin Minghao Dang Xiuning Le Can Hu Qing Deng Ansam Sinjab Pravesh Gupta Ruiping Wang Dapeng Hao Fuduan Peng Xinmiao Yan Yunhe Liu Shumei Song Shaojun Zhang John V Heymach Alexandre Reuben Yasir Y Elamin Melissa P Pizzi Yang Lu Rossana Lazcano Jian Hu Mingyao Li Michael Curran Andrew Futreal Anirban Maitra Amir A Jazaeri Jaffer A Ajani Charles Swanton Xiang-Dong Cheng Hussein A Abbas Maura Gillison Krishna Bhat Alexander J Lazar Michael Green Kevin Litchfield Humam Kadara Cassian Yee Linghua Wang
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Tumor-infiltrating T cells offer a promising avenue for cancer treatment, yet their states remain to be fully characterized. Here we present a single-cell atlas of T cells from 308,048 transcriptomes across 16 cancer types, uncovering previously undescribed T cell states and heterogeneous subpopulations of follicular helper, regulatory and proliferative T cells. We identified a unique stress response state, TSTR, characterized by heat shock gene expression. TSTR cells are detectable in situ in the tumor microenvironment across various cancer types, mostly within lymphocyte aggregates or potential tertiary lymphoid structures in tumor beds or surrounding tumor edges. T cell states/compositions correlated with genomic, pathological and clinical features in 375 patients from 23 cohorts, including 171 patients who received immune checkpoint blockade therapy. We also found significantly upregulated heat shock gene expression in intratumoral CD4/CD8+ cells following immune checkpoint blockade treatment, particularly in nonresponsive tumors, suggesting a potential role of TSTR cells in immunotherapy resistance. Our well-annotated T cell reference maps, web portal and automatic alignment/annotation tool could provide valuable resources for T cell therapy optimization and biomarker discovery.
Journal Nature Medicine
Issue number 6