Impaired activation of plasmacytoid dendritic cells via Toll-Like receptor 7/9 and STING is mediated by melanoma-derived immunosuppressive cytokines and metabolic drift.

Plasmacytoid dendritic cells (pDCs) infiltrate a large set of human cancers. IFN-a produced by pDCs might induce growth arrest and apoptosis in tumor cells and modulates innate and adaptive immune cells involved in anti-cancer immunity. Moreover, pDC-derived effector molecules exert tumor cell killing. However, the activation state and clinical relevance of pDCs infiltration in cancer is still largely controversial. In Primary Cutaneous Melanoma (PCM), pDCs density decreases over disease progression and collapses in metastatic melanoma (MM). Moreover, the residual circulating pDC compartment is defective in IFN-a production. Here, based on a set of microscopic, functional and in silico analysis, we demonstrated that the melanoma secretome directly impairs type I interferon and CXCL10 production by pDCs via TLR-7/9 and cGAS-STING signaling pathways. As proposed byBased on bulk transcriptomic data, we could confirmed that TGF-ß and a metabolic drift represent relevant mechanisms enforcing pDC-mediated melanoma escape. Overall design: Bulk RNA sequencing (RNA-seq) analysis of healthy pDCs, cultured in RPMI or in melanoma conditioned medium (SN-mel146; SN-mel336 ) and either left untreated or stimulated with R848 for 2 hours.