Lei et al. showed that anti-CD3/CD28-stimulated CD4+ T cells induced purified human blood cDC1s and less responsive cDC2s (but not pDCs and moDCs) to express antigen presentation, costimulation, cytokine, and chemokine gene/protein signatures more strongly than PRR signaling. CD4+ T cell-signaled cDC1s were the most potent DCs in an in vitro assay of CTL priming by (tumor) cell-associated antigens, and expressed the clinically favorable DC3 and mregDC signature genes. Genes comprising the mature DC signature were associated with CD8+ and Th1 T cell and cDC1 TME infiltration and response to PD-1 blockade.
Contributed by Paula Hochman
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.