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

Chirag Krishna; Renzo G. DiNatale; Fengshen Kuo; Raghvendra M. Srivastava; Lynda Vuong; Diego Chowell; Sounak Gupta; Chad Vanderbilt; Tanaya A. Purohit; Ming Liu; Emily Kansler; Briana G. Nixon; Ying Bei Chen; Vladimir Makarov; Kyle A. Blum; Kyrollis Attalla; Stanley Weng; Michael L. Salmans; Mahdi Golkaram; Li Liu; Shile Zhang; Raakhee Vijayaraghavan; Traci Pawlowski; Victor Reuter; Maria I. Carlo; Martin H. Voss; Jonathan Coleman; Paul Russo; Robert J. Motzer; Ming O. Li; Christina S. Leslie; Timothy A. Chan; A. Ari Hakimi

doi:10.1016/j.ccell.2021.03.007

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

Chirag Krishna, Renzo G. DiNatale, Fengshen Kuo, Raghvendra M. Srivastava, Lynda Vuong, Diego Chowell, Sounak Gupta, Chad Vanderbilt, Tanaya A. Purohit, Ming Liu, Emily Kansler, Briana G. Nixon, Ying Bei Chen, Vladimir Makarov, Kyle A. Blum, Kyrollis Attalla, Stanley Weng, Michael L. Salmans, Mahdi Golkaram, Li LiuShile Zhang, Raakhee Vijayaraghavan, Traci Pawlowski, Victor Reuter, Maria I. Carlo, Martin H. Voss, Jonathan Coleman, Paul Russo, Robert J. Motzer, Ming O. Li, Christina S. Leslie, Timothy A. Chan, A. Ari Hakimi

Research output: Contribution to journal › Article › peer-review

202 Scopus citations

Abstract

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)-naïve 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.

Original language	English
Pages (from-to)	662-677.e6
Journal	Cancer Cell
Volume	39
Issue number	5
DOIs	https://doi.org/10.1016/j.ccell.2021.03.007
State	Published - 10 May 2021
Externally published	Yes

Keywords

TCR sequencing
immunotherapy
pathology
renal cell carcinoma
single-cell RNA-sequencing
tissue-resident
tumor-associated macrophages
tyrosine kinase inhibitors

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10.1016/j.ccell.2021.03.007

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Krishna, C., DiNatale, R. G., Kuo, F., Srivastava, R. M., Vuong, L., Chowell, D., Gupta, S., Vanderbilt, C., Purohit, T. A., Liu, M., Kansler, E., Nixon, B. G., Chen, Y. B., Makarov, V., Blum, K. A., Attalla, K., Weng, S., Salmans, M. L., Golkaram, M., ... Hakimi, A. A. (2021). Single-cell sequencing links multiregional immune landscapes and tissue-resident T cells in ccRCC to tumor topology and therapy efficacy. Cancer Cell, 39(5), 662-677.e6. https://doi.org/10.1016/j.ccell.2021.03.007

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

abstract = "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)-na{\"i}ve 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.",

keywords = "TCR sequencing, immunotherapy, pathology, renal cell carcinoma, single-cell RNA-sequencing, tissue-resident, tumor-associated macrophages, tyrosine kinase inhibitors",

author = "Chirag Krishna and DiNatale, {Renzo G.} and Fengshen Kuo and Srivastava, {Raghvendra M.} and Lynda Vuong and Diego Chowell and Sounak Gupta and Chad Vanderbilt and Purohit, {Tanaya A.} and Ming Liu and Emily Kansler and Nixon, {Briana G.} and Chen, {Ying Bei} and Vladimir Makarov and Blum, {Kyle A.} and Kyrollis Attalla and Stanley Weng and Salmans, {Michael L.} and Mahdi Golkaram and Li Liu and Shile Zhang and Raakhee Vijayaraghavan and Traci Pawlowski and Victor Reuter and Carlo, {Maria I.} and Voss, {Martin H.} and Jonathan Coleman and Paul Russo and Motzer, {Robert J.} and Li, {Ming O.} and Leslie, {Christina S.} and Chan, {Timothy A.} and Hakimi, {A. Ari}",

note = "Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",

year = "2021",

month = may,

day = "10",

doi = "10.1016/j.ccell.2021.03.007",

language = "English",

volume = "39",

pages = "662--677.e6",

journal = "Cancer Cell",

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Krishna, C, DiNatale, RG, Kuo, F, Srivastava, RM, Vuong, L, Chowell, D, Gupta, S, Vanderbilt, C, Purohit, TA, Liu, M, Kansler, E, Nixon, BG, Chen, YB, Makarov, V, Blum, KA, Attalla, K, Weng, S, Salmans, ML, Golkaram, M, Liu, L, Zhang, S, Vijayaraghavan, R, Pawlowski, T, Reuter, V, Carlo, MI, Voss, MH, Coleman, J, Russo, P, Motzer, RJ, Li, MO, Leslie, CS, Chan, TA & Hakimi, AA 2021, 'Single-cell sequencing links multiregional immune landscapes and tissue-resident T cells in ccRCC to tumor topology and therapy efficacy', Cancer Cell, vol. 39, no. 5, pp. 662-677.e6. https://doi.org/10.1016/j.ccell.2021.03.007

TY - JOUR

T1 - Single-cell sequencing links multiregional immune landscapes and tissue-resident T cells in ccRCC to tumor topology and therapy efficacy

AU - Krishna, Chirag

AU - DiNatale, Renzo G.

AU - Kuo, Fengshen

AU - Srivastava, Raghvendra M.

AU - Vuong, Lynda

AU - Chowell, Diego

AU - Gupta, Sounak

AU - Vanderbilt, Chad

AU - Purohit, Tanaya A.

AU - Liu, Ming

AU - Kansler, Emily

AU - Nixon, Briana G.

AU - Chen, Ying Bei

AU - Makarov, Vladimir

AU - Blum, Kyle A.

AU - Attalla, Kyrollis

AU - Weng, Stanley

AU - Salmans, Michael L.

AU - Golkaram, Mahdi

AU - Liu, Li

AU - Zhang, Shile

AU - Vijayaraghavan, Raakhee

AU - Pawlowski, Traci

AU - Reuter, Victor

AU - Carlo, Maria I.

AU - Voss, Martin H.

AU - Coleman, Jonathan

AU - Russo, Paul

AU - Motzer, Robert J.

AU - Li, Ming O.

AU - Leslie, Christina S.

AU - Chan, Timothy A.

AU - Hakimi, A. Ari

PY - 2021/5/10

Y1 - 2021/5/10

N2 - 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)-naïve 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.

AB - 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)-naïve 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.

KW - TCR sequencing

KW - immunotherapy

KW - pathology

KW - renal cell carcinoma

KW - single-cell RNA-sequencing

KW - tissue-resident

KW - tumor-associated macrophages

KW - tyrosine kinase inhibitors

UR - http://www.scopus.com/inward/record.url?scp=85104966318&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2021.03.007

DO - 10.1016/j.ccell.2021.03.007

M3 - Article

C2 - 33861994

AN - SCOPUS:85104966318

SN - 1535-6108

VL - 39

SP - 662-677.e6

JO - Cancer Cell

JF - Cancer Cell

IS - 5

ER -

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

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Keywords

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