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

Cell. 2020 Jun 25;181(7):1612-1625.e13. doi: 10.1016/j.cell.2020.05.017. Epub 2020 Jun 3.

Authors

David Y Oh¹, Serena S Kwek¹, Siddharth S Raju², Tony Li¹, Elizabeth McCarthy³, Eric Chow⁴, Dvir Aran⁵, Arielle Ilano¹, Chien-Chun Steven Pai¹, Chiara Rancan¹, Kathryn Allaire¹, Arun Burra¹, Yang Sun³, Matthew H Spitzer⁶, Serghei Mangul⁷, Sima Porten⁸, Maxwell V Meng⁸, Terence W Friedlander¹, Chun Jimmie Ye⁹, Lawrence Fong¹⁰

Affiliations

¹ Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
² Division of Rheumatology, Department of Medicine; Department of Epidemiology and Biostatistics; and Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Otolaryngology - Head and Neck Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
³ Division of Rheumatology, Department of Medicine; Department of Epidemiology and Biostatistics; and Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA.
⁴ Department of Biochemistry and Biophysics, Center for Advanced Technologies, University of California, San Francisco, San Francisco, CA 94143, USA.
⁵ Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
⁶ Parker Institute for Cancer Immunotherapy, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Otolaryngology - Head and Neck Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
⁷ Department of Computer Science, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁸ Department of Urology, University of California, San Francisco, San Francisco, CA 94143, USA.
⁹ Parker Institute for Cancer Immunotherapy, University of California, San Francisco, San Francisco, CA 94143, USA; Division of Rheumatology, Department of Medicine; Department of Epidemiology and Biostatistics; and Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA; Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA 94143, USA; Chan Zuckerberg Biohub, San Francisco, CA, USA. Electronic address: jimmie.ye@ucsf.edu.
¹⁰ Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Parker Institute for Cancer Immunotherapy, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: lawrence.fong@ucsf.edu.

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.

Trial registration: ClinicalTrials.gov NCT02451423.

Keywords: Bladder cancer; PD-1 blockade; anti-PD-L1; checkpoint inhibition; cytotoxic CD4(+) T cells; predictive gene signature; single-cell sequencing.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

B7-H1 Antigen / genetics
B7-H1 Antigen / immunology
Biomarkers, Pharmacological / analysis
CD4-Positive T-Lymphocytes / immunology
CD4-Positive T-Lymphocytes / metabolism*
CD8-Positive T-Lymphocytes / immunology
CD8-Positive T-Lymphocytes / metabolism
Gene Expression Regulation, Neoplastic / genetics
Genes, MHC Class II
Humans
Immune Checkpoint Inhibitors / pharmacology
Immunotherapy
Lymphocytes, Tumor-Infiltrating
Programmed Cell Death 1 Receptor / genetics
Receptors, Antigen, T-Cell / genetics
Single-Cell Analysis / methods
T-Lymphocytes, Regulatory
Urinary Bladder Neoplasms / genetics*
Urinary Bladder Neoplasms / immunology
Urinary Bladder Neoplasms / metabolism*

Substances

B7-H1 Antigen
Biomarkers, Pharmacological
Immune Checkpoint Inhibitors
Programmed Cell Death 1 Receptor
Receptors, Antigen, T-Cell

Associated data

ClinicalTrials.gov/NCT02451423

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding