Pan-cancer mapping of single CD8+ T cell profiles reveals a TCF1:CXCR6 axis regulating CD28 co-stimulation and anti-tumor immunity I

Cytotoxic CD8+ T cells need to persist and function in diverse tumor microenvironments to exert their effects. Here, we developed Generalizable Matrix Decomposition Framework (GMDF), a matrix factorization algorithm that recovers both shared and tumor type-specific transcriptional programs from diverse data sets, and applied it to a scRNA-seq compendium of 38,852 CD8+ T cells from 141 patients spanning nine different human cancers. Our meta-single-cell analyses uncovered a pan-cancer T cell dysfunction program that was predictive of clinical responses to checkpoint blockade in melanoma and highlighted CXCR6 as a pan-cancer marker of chronically activated T cells. CXCR6 transcription was activated by AP-1 factors and repressed by TCF1. In mouse models, CXCR6 expression increased with tumor progression and upon checkpoint blockade. CXCR6 deletion in CD8+ T cells increased apoptosis of PD1+Tim3+ cells and compromised tumor growth control due to suppressed expression of survival factors and CD28 co-stimulation, revealing a role for CXCR6 in opposing PD1-mediated suppression of CD28 signaling. Our application of GMDF led us to discover a TCF1:CXCR6 axis that counterbalances PD1-mediated suppression of CD8+ cell responses and is essential for effective anti-tumor immunity.