CD4 + T-cell help explains clinical benefit of specific intra-tumoral dendritic cell states in human cancer

Classical type 1 dendritic cells (cDC1) have a low abundance in the tumor microenvironment (TME), but positively correlate with patient survival. We hypothesized that the ability of cDC1 to relay CD4+ T-cell help for the cytotoxic T lymphocyte (CTL) response explains their clinical benefit. In vitro, contact with activated CD4+ T-cells enabled human cDC1, but no other DC types, to induce a CTL response to cell-associated tumor antigens. Single cell transcriptomics revealed that CD4+ T-cell help uniquely optimized cDC1 and no other DC types in many functions that support antigen cross-presentation and T-cell priming. We robustly identified “helped” cDC1 in a multitude of human cancer types by the overlap in their transcriptomic signature with that of recently defined, positively prognostic tumor-infiltrating DC states. As predicted from the functional effects of CD4+ T-cell help, the transcriptomic signature of “helped” cDC1 correlated with tumor infiltration by CTL and Thelper(h)-1 cells, overall survival and response to PD-1-targeting immunotherapy. These findings reveal a critical role of CD4+ T-cell help delivery via cDC1 to CTL in the TME PBMCs from 3 healthy donors were stained with the appropriate antibodies and within the live CD3-CD19-HLA-DR+ population, pDC (CD11c-CD14-CD303+), cDC1 (CD11c+CD14-CD141+), cDC2 (CD11c+CD14-CD1c+), and moDC (CD11c+CD14+CD1c+CD206+) were sorted, RNA was isolated, cDNA was generated and sequenced.