Tooley and Jerby-Arnon et al. developed a new generalizable matrix decomposition framework for scRNAseq data to map CD8+ T cell gene expression programs from over 33,000 cells across seven different human cancers. They identified a pan-cancer T cell dysfunction program that predicts clinical non-response to immunotherapy. CXCR6 expression was enriched upon ICB and was a pan-cancer marker of terminally dysfunctional CD8+ T cells, repressed by TCF1. In a melanoma mouse model, CXCR6-deficient CD8+ T cells showed decreased expression of Tox, Bcl2, and CD28, promoted apoptosis in PD1+TIM3+ CD8+ TILs, and diminished tumor control.
Contributed by Shishir Pant
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.
Author Info: (1) The 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
Author Info: (1) The 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. (2) Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: ljerby@stanford.edu. (3) The Gene Lay Institute of Immunology and Inflammation of Brigham and Women's Hospital, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. (4) The Gene Lay Institute of Immunology and Inflammation of Brigham and Women's Hospital, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. (5) The Gene Lay Institute of Immunology and Inflammation of Brigham and Women's Hospital, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. (6) The Gene Lay Institute of Immunology and Inflammation of Brigham and Women's Hospital, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. (7) The Gene Lay Institute of Immunology and Inflammation of Brigham and Women's Hospital, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. (8) Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. (9) Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. (10) The Gene Lay Institute of Immunology and Inflammation of Brigham and Women's Hospital, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. (11) The Gene Lay Institute of Immunology and Inflammation of Brigham and Women's Hospital, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. (12) Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. (13) Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Howard Hughes Medical Institute and Koch Institute of Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. Electronic address: regev.aviv@gene.com. (14) The Gene Lay Institute of Immunology and Inflammation of Brigham and Women's Hospital, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: acanderson@bwh.harvard.edu.
