Single-cell sequencing links multiregional immune landscapes and tissue-resident T cells in ccRCC to tumor topology and therapy efficacy

被引：228

作者：

Krishna, Chirag ^{[1
]}

DiNatale, Renzo G. ^{[2
,3
,4
]}

Kuo, Fengshen ^{[2
]}

Srivastava, Raghvendra M. ^{[2
]}

Vuong, Lynda ^{[2
,4
]}

Chowell, Diego ^{[2
,4
]}

Gupta, Sounak ^{[8
]}

Vanderbilt, Chad ^{[8
]}

Purohit, Tanaya A. ^{[2
]}

Liu, Ming ^{[5
]}

Kansler, Emily ^{[5
,6
]}

Nixon, Briana G. ^{[5
,7
]}

Chen, Ying-Bei ^{[8
]}

Makarov, Vladimir ^{[2
,4
]}

Blum, Kyle A. ^{[2
,3
,4
]}

Attalla, Kyrollis ^{[3
]}

Weng, Stanley ^{[3
]}

Salmans, Michael L. ^{[9
]}

Golkaram, Mahdi ^{[9
]}

Liu, Li ^{[9
]}

Zhang, Shile ^{[9
]}

Vijayaraghavan, Raakhee ^{[9
]}

Pawlowski, Traci ^{[9
]}

Reuter, Victor ^{[8
]}

Carlo, Maria, I ^{[10
]}

Voss, Martin H. ^{[10
]}

Coleman, Jonathan ^{[3
]}

Russo, Paul ^{[3
]}

Motzer, Robert J. ^{[10
]}

Li, Ming O. ^{[5
]}

Leslie, Christina S. ^{[1
]}

Chan, Timothy A. ^{[2
,11
,12
,13
,14
]}

Hakimi, A. Ari ^{[2
,3
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Computat & Syst Biol Program, New York, NY 10065 USA

[2] Mem Sloan Kettering Canc Ctr, Lmmunogen & Precis Oncol Platform, New York, NY 10065 USA

[3] Mem Sloan Kettering Canc Ctr, Dept Surg, Urol Serv, New York, NY 10065 USA

[4] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[5] Mem Sloan Kettering Canc Ctr, Immunol Program, New York, NY 10065 USA

[6] Mem Sloan Kettering Canc Ctr, Louis V Gerstner Jr Grad Sch Biomed Sci, New York, NY 10065 USA

[7] Cornell Univ, Weill Cornell Grad Sch Med Sci, Immunol & Microbial Pathogenesis Program, New York, NY 10065 USA

[8] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA

[9] IIlumina Inc, San Diego, CA 92122 USA

[10] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA

[11] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, New York, NY 10065 USA

[12] Cleveland Clin, Ctr Immunotherapy & Precis Immunooncol, Cleveland, OH 44195 USA

[13] Cleveland Clin, Lerner Res Inst, Cleveland, OH 44195 USA

[14] Cleveland Clin, Natl Ctr Regenerat Med, Cleveland, OH 44195 USA

来源：

CANCER CELL | 2021年 / 39卷 / 05期

关键词：

DENDRITIC CELLS; OPEN-LABEL; CANCER; MACROPHAGES; LINEAGE; IDENTIFICATION; LYMPHOCYTES; METASTASIS; CARCINOMA; AXITINIB;

D O I：

10.1016/j.ccell.2021.03.007

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Clear cell renal cell carcinomas (ccRCCs) are highly immune infiltrated, but the effect of immune heterogeneity on clinical outcome in ccRCC has not been fully characterized. Here we perform paired single-cell RNA (scRNA) and T cell receptor (TCR) sequencing of 167,283 cells from multiple tumor regions, lymph node, normal kidney, and peripheral blood of two immune checkpoint blockade (ICB)-naive and four ICB-treated patients to map the ccRCC immune landscape. We detect extensive heterogeneity within and between patients, with enrichment of CD8A(+) tissue-resident T cells in a patient responsive to ICB and tumor-associated macrophages (TAMs) in a resistant patient. A TCR trajectory framework suggests distinct T cell differentiation pathways between patients responding and resistant to ICB. Finally, scRNA-derived signatures of tissue-resident T cells and TAMs are associated with response to ICB and targeted therapies across multiple independent cohorts. Our study establishes a multimodal interrogation of the cellular programs underlying therapeutic efficacy in ccRCC.

引用

页码：662 / +

页数：22

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