{Reference Type}: Journal Article
{Title}: Pan-cancer mapping of single CD8+ T cell profiles reveals a TCF1:CXCR6 axis regulating CD28 co-stimulation and anti-tumor immunity.
{Author}: Tooley K;Jerby L;Escobar G;Krovi SH;Mangani D;Dandekar G;Cheng H;Madi A;Goldschmidt E;Lambden C;Krishnan RK;Rozenblatt-Rosen O;Regev A;Anderson AC;
{Journal}: Cell Rep Med
{Volume}: 0
{Issue}: 0
{Year}: 2024 Jun 26
{Factor}: 16.988
{DOI}: 10.1016/j.xcrm.2024.101640
{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.