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 journalArticlepeer-review


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 languageEnglish
Pages (from-to)1612-1625.e13
Issue number7
StatePublished - 25 Jun 2020
Externally publishedYes


  • 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


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