A Lactate-induced SREBF2-dependent genetic program drives an immunotolerant dendritic cell population during cancer progression [scRNAseq_mouse]

Dendritic cells (cDCs) are essential mediators of anti-tumor immunity. Cancers have developed mechanisms to render DCs dysfunctional within the tumor microenvironment. Utilizing CD63 as a unique surface marker, we demonstrate that mature regulatory DCs (mregDCs) suppress DC antigen cross-presentation while driving TH2 and regulatory T cell differentiation within tumor-draining lymph node tissues. Transcriptional and metabolic studies show that mregDC functionality is dependent upon the mevalonate biosynthetic pathway and the master transcription factor, SREBP2. Melanoma-derived lactate activates DC SREBP2 in the tumor microenvironment (TME) and drives mregDC development from conventional DCs. DC-specific genetic silencing and pharmacologic inhibition of SREBP2 promotes anti-tumor CD8+ T cell activation and suppresses melanoma progression. CD63+ mregDCs reside within the sentinel lymph nodes of melanoma patients. Collectively, this work describes a tumor-driven SREBP2-dependent program that promotes CD63+ mregDC development and function while serving as a promising therapeutic target for overcoming immune tolerance in the TME. scRNAseq of dendritic cells (DCs) sorted from the tumor draining lymph node or non-draining lymph node of Tyrosinase-driven Cre Recombinase BRAFV600E, PTEN-/- mice on a C57Bl6 background, as well as Dcs sorted from the inguinal lymph node of non-tumor bearing wildtype mice. Additionally, scATACseq was performed on DCs sorted from the tumor draining lymph node of Tyrosinase-driven Cre Recombinase BRAFV600E, PTEN-/- mice. scRNAseq was also performed on dendritic cells sorted from the sentinel lymph node of human melanoma patients in addition to spatial transcriptomics of the sentinel lymph node of human melanoma patients.