Abstract
CD8+ T cells must persist and function in diverse tumor microenvironments to exert their effects. Thus, understanding common underlying expression programs could better inform the next generation of immunotherapies. We apply a generalizable matrix factorization algorithm that recovers both shared and context-specific expression programs from diverse datasets to a single-cell RNA sequencing (scRNA-seq) compendium of 33,161 CD8+ T cells from 132 patients with seven human cancers. Our meta-single-cell analyses uncover a pan-cancer T cell dysfunction program that predicts clinical non-response to checkpoint blockade in melanoma and highlights CXCR6 as a pan-cancer marker of chronically activated T cells. Cxcr6 is trans-activated by AP-1 and repressed by TCF1. Using mouse models, we show that Cxcr6 deletion in CD8+ T cells increases apoptosis of PD1+TIM3+ cells, dampens CD28 signaling, and compromises tumor growth control. Our study uncovers a TCF1:CXCR6 axis that counterbalances PD1-mediated suppression of CD8+ cell responses and is essential for effective anti-tumor immunity.
Original language | English |
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Article number | 101640 |
Journal | Cell Reports Medicine |
Volume | 5 |
Issue number | 7 |
DOIs | |
State | Published - 16 Jul 2024 |
Keywords
- CD28
- CXCR6
- T cell dysfunction
- T cell exhaustion
- TCF1
- human
- meta-analysis
- pan-cancer
- single cell
All Science Journal Classification (ASJC) codes
- General Biochemistry,Genetics and Molecular Biology