CD4+ helper T cells endow cDC1 with cancer-impeding functions in the human tumor micro-environment

Abstract Despite their low abundance in the tumor microenvironment (TME), classical type 1 dendritic cells (cDC1) play a pivotal role in anti-cancer immunity, and their abundance positively correlates with patient survival. However, their interaction with CD4 + T-cells to potentially enable the cytotoxic T lymphocyte (CTL) response has not been elucidated. Here we show that contact with activated CD4 + T-cells enables human ex vivo cDC1, but no other DC types, to induce a CTL response to cell-associated tumor antigens. Single cell transcriptomics reveals that CD4 + T-cell help uniquely optimizes cDC1 in many functions that support antigen cross-presentation and T-cell priming, while these changes don’t apply to other DC types. We robustly identify “helped” cDC1 in the TME of a multitude of human cancer types by the overlap in their transcriptomic signature with that of recently defined, tumor-infiltrating DC states that prove to be positively prognostic. As predicted from the functional effects of CD4 + T-cell help, the transcriptomic signature of “helped” cDC1 correlates with tumor infiltration by CTLs and Thelper(h)−1 cells, overall survival and response to PD-1-targeting immunotherapy. These findings reveal a critical role for CD4 + T-cell help in enabling cDC1 function in the TME and may establish the helped cDC1 transcriptomic signature as diagnostic marker in cancer.