Intratumoral CD4+ T Cells Mediate Anti-tumor Cytotoxicity in Human Bladder Cancer

David Y. Oh; Serena S. Kwek; Siddharth S. Raju; Tony Li; Elizabeth McCarthy; Eric Chow; Dvir Aran; Arielle Ilano; Chien Chun Steven Pai; Chiara Rancan; Kathryn Allaire; Arun Burra; Yang Sun; Matthew H. Spitzer; Serghei Mangul; Sima Porten; Maxwell V. Meng; Terence W. Friedlander; Chun Jimmie Ye; Lawrence Fong

doi:10.1016/j.cell.2020.05.017

Intratumoral CD4⁺ T Cells Mediate Anti-tumor Cytotoxicity in Human Bladder Cancer

David Y. Oh, Serena S. Kwek, Siddharth S. Raju, Tony Li, Elizabeth McCarthy, Eric Chow, Dvir Aran, Arielle Ilano, Chien Chun Steven Pai, Chiara Rancan, Kathryn Allaire, Arun Burra, Yang Sun, Matthew H. Spitzer, Serghei Mangul, Sima Porten, Maxwell V. Meng, Terence W. Friedlander, Chun Jimmie Ye, Lawrence Fong

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

Abstract

Responses to anti-PD-1 immunotherapy occur but are infrequent in bladder cancer. The specific T cells that mediate tumor rejection are unknown. T cells from human bladder tumors and non-malignant tissue were assessed with single-cell RNA and paired T cell receptor (TCR) sequencing of 30,604 T cells from 7 patients. We find that the states and repertoires of CD8⁺ T cells are not distinct in tumors compared with non-malignant tissues. In contrast, single-cell analysis of CD4⁺ T cells demonstrates several tumor-specific states, including multiple distinct states of regulatory T cells. Surprisingly, we also find multiple cytotoxic CD4⁺ T cell states that are clonally expanded. These CD4⁺ T cells can kill autologous tumors in an MHC class II-dependent fashion and are suppressed by regulatory T cells. Further, a gene signature of cytotoxic CD4⁺ T cells in tumors predicts a clinical response in 244 metastatic bladder cancer patients treated with anti-PD-L1.

Original language	English
Pages (from-to)	1612-1625.e13
Journal	Cell
Volume	181
Issue number	7
DOIs	https://doi.org/10.1016/j.cell.2020.05.017
State	Published - 25 Jun 2020
Externally published	Yes

Keywords

Bladder cancer
PD-1 blockade
anti-PD-L1
checkpoint inhibition
cytotoxic CD4 T cells
predictive gene signature
single-cell sequencing

All Science Journal Classification (ASJC) codes

General Biochemistry,Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.cell.2020.05.017

Cite this

Oh, D. Y., Kwek, S. S., Raju, S. S., Li, T., McCarthy, E., Chow, E., Aran, D., Ilano, A., Pai, C. C. S., Rancan, C., Allaire, K., Burra, A., Sun, Y., Spitzer, M. H., Mangul, S., Porten, S., Meng, M. V., Friedlander, T. W., Ye, C. J., & Fong, L. (2020). Intratumoral CD4⁺ T Cells Mediate Anti-tumor Cytotoxicity in Human Bladder Cancer. Cell, 181(7), 1612-1625.e13. https://doi.org/10.1016/j.cell.2020.05.017

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title = "Intratumoral CD4+ T Cells Mediate Anti-tumor Cytotoxicity in Human Bladder Cancer",

abstract = "Responses to anti-PD-1 immunotherapy occur but are infrequent in bladder cancer. The specific T cells that mediate tumor rejection are unknown. T cells from human bladder tumors and non-malignant tissue were assessed with single-cell RNA and paired T cell receptor (TCR) sequencing of 30,604 T cells from 7 patients. We find that the states and repertoires of CD8+ T cells are not distinct in tumors compared with non-malignant tissues. In contrast, single-cell analysis of CD4+ T cells demonstrates several tumor-specific states, including multiple distinct states of regulatory T cells. Surprisingly, we also find multiple cytotoxic CD4+ T cell states that are clonally expanded. These CD4+ T cells can kill autologous tumors in an MHC class II-dependent fashion and are suppressed by regulatory T cells. Further, a gene signature of cytotoxic CD4+ T cells in tumors predicts a clinical response in 244 metastatic bladder cancer patients treated with anti-PD-L1.",

keywords = "Bladder cancer, PD-1 blockade, anti-PD-L1, checkpoint inhibition, cytotoxic CD4 T cells, predictive gene signature, single-cell sequencing",

author = "Oh, {David Y.} and Kwek, {Serena S.} and Raju, {Siddharth S.} and Tony Li and Elizabeth McCarthy and Eric Chow and Dvir Aran and Arielle Ilano and Pai, {Chien Chun Steven} and Chiara Rancan and Kathryn Allaire and Arun Burra and Yang Sun and Spitzer, {Matthew H.} and Serghei Mangul and Sima Porten and Meng, {Maxwell V.} and Friedlander, {Terence W.} and Ye, {Chun Jimmie} and Lawrence Fong",

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year = "2020",

month = jun,

day = "25",

doi = "10.1016/j.cell.2020.05.017",

language = "الإنجليزيّة",

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Oh, DY, Kwek, SS, Raju, SS, Li, T, McCarthy, E, Chow, E, Aran, D, Ilano, A, Pai, CCS, Rancan, C, Allaire, K, Burra, A, Sun, Y, Spitzer, MH, Mangul, S, Porten, S, Meng, MV, Friedlander, TW, Ye, CJ & Fong, L 2020, 'Intratumoral CD4⁺ T Cells Mediate Anti-tumor Cytotoxicity in Human Bladder Cancer', Cell, vol. 181, no. 7, pp. 1612-1625.e13. https://doi.org/10.1016/j.cell.2020.05.017

TY - JOUR

T1 - Intratumoral CD4+ T Cells Mediate Anti-tumor Cytotoxicity in Human Bladder Cancer

AU - Oh, David Y.

AU - Kwek, Serena S.

AU - Raju, Siddharth S.

AU - Li, Tony

AU - McCarthy, Elizabeth

AU - Chow, Eric

AU - Aran, Dvir

AU - Ilano, Arielle

AU - Pai, Chien Chun Steven

AU - Rancan, Chiara

AU - Allaire, Kathryn

AU - Burra, Arun

AU - Sun, Yang

AU - Spitzer, Matthew H.

AU - Mangul, Serghei

AU - Porten, Sima

AU - Meng, Maxwell V.

AU - Friedlander, Terence W.

AU - Ye, Chun Jimmie

AU - Fong, Lawrence

PY - 2020/6/25

Y1 - 2020/6/25

N2 - Responses to anti-PD-1 immunotherapy occur but are infrequent in bladder cancer. The specific T cells that mediate tumor rejection are unknown. T cells from human bladder tumors and non-malignant tissue were assessed with single-cell RNA and paired T cell receptor (TCR) sequencing of 30,604 T cells from 7 patients. We find that the states and repertoires of CD8+ T cells are not distinct in tumors compared with non-malignant tissues. In contrast, single-cell analysis of CD4+ T cells demonstrates several tumor-specific states, including multiple distinct states of regulatory T cells. Surprisingly, we also find multiple cytotoxic CD4+ T cell states that are clonally expanded. These CD4+ T cells can kill autologous tumors in an MHC class II-dependent fashion and are suppressed by regulatory T cells. Further, a gene signature of cytotoxic CD4+ T cells in tumors predicts a clinical response in 244 metastatic bladder cancer patients treated with anti-PD-L1.

AB - Responses to anti-PD-1 immunotherapy occur but are infrequent in bladder cancer. The specific T cells that mediate tumor rejection are unknown. T cells from human bladder tumors and non-malignant tissue were assessed with single-cell RNA and paired T cell receptor (TCR) sequencing of 30,604 T cells from 7 patients. We find that the states and repertoires of CD8+ T cells are not distinct in tumors compared with non-malignant tissues. In contrast, single-cell analysis of CD4+ T cells demonstrates several tumor-specific states, including multiple distinct states of regulatory T cells. Surprisingly, we also find multiple cytotoxic CD4+ T cell states that are clonally expanded. These CD4+ T cells can kill autologous tumors in an MHC class II-dependent fashion and are suppressed by regulatory T cells. Further, a gene signature of cytotoxic CD4+ T cells in tumors predicts a clinical response in 244 metastatic bladder cancer patients treated with anti-PD-L1.

KW - Bladder cancer

KW - PD-1 blockade

KW - anti-PD-L1

KW - checkpoint inhibition

KW - cytotoxic CD4 T cells

KW - predictive gene signature

KW - single-cell sequencing

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U2 - 10.1016/j.cell.2020.05.017

DO - 10.1016/j.cell.2020.05.017

M3 - مقالة

C2 - 32497499

SN - 0092-8674

VL - 181

SP - 1612-1625.e13

JO - Cell

JF - Cell

IS - 7

ER -