Pan-cancer T cell atlas links a cellular stress response state to immunotherapy resistance

被引：119

作者：

Chu, Yanshuo ^{[1
]}

Dai, Enyu ^{[1
]}

Li, Yating ^{[1
,2
]}

Han, Guangchun ^{[1
]}

Pei, Guangsheng ^{[1
]}

Ingram, Davis R. R. ^{[3
]}

Thakkar, Krupa ^{[4
]}

Qin, Jiang-Jiang ^{[5
,6
]}

Dang, Minghao ^{[1
]}

Le, Xiuning ^{[7
]}

Hu, Can ^{[5
,6
]}

Deng, Qing ^{[8
]}

Sinjab, Ansam ^{[3
]}

Gupta, Pravesh ^{[3
]}

Wang, Ruiping ^{[1
]}

Hao, Dapeng ^{[1
]}

Peng, Fuduan ^{[1
]}

Yan, Xinmiao ^{[1
]}

Liu, Yunhe ^{[1
]}

Song, Shumei ^{[9
]}

Zhang, Shaojun ^{[1
]}

Heymach, John V. V. ^{[7
]}

Reuben, Alexandre ^{[7
]}

Elamin, Yasir Y. Y. ^{[7
]}

Pizzi, Melissa P. P. ^{[9
]}

Lu, Yang ^{[10
]}

Lazcano, Rossana ^{[3
]}

Hu, Jian ^{[11
]}

Li, Mingyao ^{[12
]}

Curran, Michael ^{[13
]}

Futreal, Andrew ^{[1
]}

Maitra, Anirban ^{[14
]}

Jazaeri, Amir A. A. ^{[15
]}

Ajani, Jaffer A. A. ^{[9
]}

Swanton, Charles ^{[16
,17
]}

Cheng, Xiang-Dong ^{[5
,6
]}

Abbas, Hussein A. A. ^{[18
]}

Gillison, Maura ^{[7
]}

Bhat, Krishna ^{[3
]}

Lazar, Alexander J. J. ^{[1
,3
,14
,19
]}

Green, Michael ^{[1
,8
]}

Litchfield, Kevin ^{[4
,17
]}

Kadara, Humam ^{[3
,19
]}

Yee, Cassian ^{[2
,13
]}

Wang, Linghua ^{[1
,19
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Melanoma Med Oncol, Houston, TX USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX USA

[4] Univ Coll London Canc Inst, Tumour Immunogen & Immunosurveillance Lab, London, England

[5] Univ Chinese Acad Sci, Zhejiang Canc Hosp, Dept Gastr Surg, Canc Hosp, Hangzhou, Peoples R China

[6] Chinese Acad Sci, Inst Basic Med & Canc, Hangzhou, Peoples R China

[7] Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Houston, TX USA

[8] Univ Texas MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, Houston, TX USA

[9] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX USA

[10] Univ Texas MD Anderson Canc Ctr, Dept Nucl Med, Houston, TX USA

[11] Emory Sch Med, Dept Human Genet, Atlanta, GA USA

[12] Univ Penn, Perelman Sch Med, Dept Biostat Epidemiol & Informat, Philadelphia, PA USA

[13] Univ Texas MD Anderson Canc Ctr, Dept Immunol, Houston, TX USA

[14] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX USA

[15] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol & Reprod Med, Houston, TX USA

[16] Francis Crick Inst, Canc Evolut & Genome Instabil Lab, London, England

[17] Univ Coll London Canc Inst, Canc Res UK Lung Canc Ctr Excellence, London, England

[18] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX USA

[19] Univ Texas MD Anderson Canc Ctr UTHlth Houston, Grad Sch Biomed Sci, Houston, TX 77030 USA

来源：

NATURE MEDICINE | 2023年 / 29卷 / 06期

基金：

英国医学研究理事会; 英国惠康基金; 美国国家卫生研究院;

关键词：

TGF-BETA; TUMOR; LANDSCAPE; MECHANISMS; EXCLUSION;

D O I：

10.1038/s41591-023-02371-y

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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, T-STR, characterized by heat shock gene expression. T-STR 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 T-STR 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. A single-cell analysis of tumor-infiltrating T cells from 16 cancer types identifies new T cell subsets and a stress response cell state enriched in tumors resistant to immunotherapy.

引用

页码：1550 / +

页数：34

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