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Updated: Jun 22, 2025
Tumor Transplantation for Assessing the Dynamics of Tumor-Infiltrating CD8+ T Cells in Mice
Published on: June 12, 2021
Pan-cancer mapping of single CD8+ T cell profiles reveals a TCF1:CXCR6 axis regulating CD28 co-stimulation and
Katherine Tooley1, Livnat Jerby2, Giulia Escobar3
1The Gene Lay Institute of Immunology and Inflammation of Brigham and Women's Hospital, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA; Division of Medical Sciences, Harvard Medical School, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
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.
