1. Intratumoral CD4+ T Cells Mediate Anti-tumor Cytotoxicity in Human Bladder Cancer
- Author
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Matthew H. Spitzer, Sima P. Porten, Maxwell V. Meng, Chien-Chun Steven Pai, Kathryn Allaire, Serghei Mangul, Tony Li, Elizabeth E. McCarthy, Terence W. Friedlander, Chiara Rancan, Chun Jimmie Ye, Serena S. Kwek, Dvir Aran, Eric D. Chow, Lawrence Fong, Siddharth S. Raju, Yang Sun, Arielle Ilano, Arun Burra, and David Y. Oh
- Subjects
CD4-Positive T-Lymphocytes ,anti-PD-L1 ,medicine.medical_treatment ,Genes, MHC Class II ,Programmed Cell Death 1 Receptor ,Receptors, Antigen, T-Cell ,PD-1 blockade ,predictive gene signature ,CD8-Positive T-Lymphocytes ,single-cell sequencing ,Biology ,T-Lymphocytes, Regulatory ,B7-H1 Antigen ,Biomarkers, Pharmacological ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Lymphocytes, Tumor-Infiltrating ,0302 clinical medicine ,checkpoint inhibition ,MHC class I ,cytotoxic CD4+ T cells ,medicine ,Humans ,Cytotoxic T cell ,Receptor ,Immune Checkpoint Inhibitors ,030304 developmental biology ,0303 health sciences ,Bladder cancer ,T-cell receptor ,Cancer ,Immunotherapy ,medicine.disease ,Gene Expression Regulation, Neoplastic ,Urinary Bladder Neoplasms ,Cancer research ,biology.protein ,Single-Cell Analysis ,030217 neurology & neurosurgery ,CD8 - Abstract
Summary 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., Graphical Abstract, Highlights • Human bladder tumors contain multiple clonally expanded cytotoxic CD4+ T cell states • Cytotoxic CD4+ T cells can kill autologous tumors in an MHC class II-dependent fashion • Autologous regulatory T cells can inhibit the activity of cytotoxic CD4+ T cells • A cytotoxic CD4+ gene signature predicts response to anti-PD-L1 in bladder cancer, Single-cell RNA and paired T cell receptor sequencing highlights enrichment of cytotoxic CD4+ T cells rather than CD8+ T cells in human bladder cancer. These CD4+ T cells are capable of killing autologous tumor cells and are subjected to inhibition by Tregs.
- Published
- 2020