PD-1 blockade-driven anti-tumor CD8+ T cell immunity requires XCR1+ dendritic cells

Abstract

CD8+ T cells are required for effective anti-PD-1 (PD-1) cancer immunotherapy. Type 1 conventional dendritic cells (cDC1s) bearing XCR1 critically mediate the initiation of protective anti-tumor CD8+ T cell responses in mice and humans. However, whether cDC1s contribute to evoking the effector function of CD8+ T cells during PD-1 antibody therapy remains unclear. Here, by deleting cDC1s at the effector phase of PD-1 therapy, we identify these cells as a crucial innate determinant for effective PD-1 immunotherapy. PD-1 treatment unleashed cDC1s to promote anti-tumor CD8+ T cell immunity, through the expansion of TCF1+ precursors and generation of TIM3+ terminally differentiated effectors. Furthermore, tumor cDC1 abundance was predictive of enhanced CD8+ T cell infiltration, higher survival, and improved clinical responses to PD-1 therapy in human cancer patients. Together, this study reveals the requirement for cDC1s in PD-1 blockade therapy, through their ability to elicit CD8+ T cell effector responses that mediate tumor control, and highlight cDC1s as an attractive cellular target to be harnessed for novel immunotherapeutics.