Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma

Moshe Sade-Feldman, Keren Yizhak, Stacey L. Bjorgaard, John P. Ray, Carl G. de Boer, Russell W. Jenkins, David J. Lieb, Jonathan H. Chen, Dennie T. Frederick, Michal Barzily-Rokni, Samuel S. Freeman, Alexandre Reuben, Paul J. Hoover, Alexandra Chloé Villani, Elena Ivanova, Andrew Portell, Patrick H. Lizotte, Amir R. Aref, Jean Pierre Eliane, Marc R. HammondHans Vitzthum, Shauna M. Blackmon, Bo Li, Vancheswaran Gopalakrishnan, Sangeetha M. Reddy, Zachary A. Cooper, Cloud P. Paweletz, David A. Barbie, Anat Stemmer-Rachamimov, Keith T. Flaherty, Jennifer A. Wargo, Genevieve M. Boland, Ryan J. Sullivan, Gad Getz, Nir Hacohen

Research output: Contribution to journalArticlepeer-review

212 Scopus citations

Abstract

Treatment of cancer has been revolutionized by immune checkpoint blockade therapies. Despite the high rate of response in advanced melanoma, the majority of patients succumb to disease. To identify factors associated with success or failure of checkpoint therapy, we profiled transcriptomes of 16,291 individual immune cells from 48 tumor samples of melanoma patients treated with checkpoint inhibitors. Two distinct states of CD8+ T cells were defined by clustering and associated with patient tumor regression or progression. A single transcription factor, TCF7, was visualized within CD8+ T cells in fixed tumor samples and predicted positive clinical outcome in an independent cohort of checkpoint-treated patients. We delineated the epigenetic landscape and clonality of these T cell states and demonstrated enhanced antitumor immunity by targeting novel combinations of factors in exhausted cells. Our study of immune cell transcriptomes from tumors demonstrates a strategy for identifying predictors, mechanisms, and targets for enhancing checkpoint immunotherapy. Single-cell analysis of immune cells from melanoma patients treated with immune checkpoint therapy uncovers a TCF7+ memory-like state in the cytotoxic T cell population and demonstrates its association with a positive outcome.

Original languageEnglish (US)
Pages (from-to)998-1013.e20
JournalCell
Volume175
Issue number4
DOIs
StatePublished - Nov 1 2018

Keywords

  • CD8 T cells
  • TCF7
  • cancer immunotherapy
  • checkpoint blockade
  • single-cell RNA-seq

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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