A SREBF2-dependent gene program drives an immunotolerant dendritic cell population during cancer progression

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. One Sentence Summary The metabolic transcription factor, SREBF2, regulates the development and tolerogenic function of the mregDC population within the tumor microenvironment. ### Competing Interest Statement B.A.H. receives research funding from Merck & Co., Tempest Therapeutics, Leap Therapeutics, Sanofi, Exicure Therapeutics, Lyell Therapeutics, and Iovance Therapeutics; consultant for Compugen; honoraria from Novartis, Merck & Co., and HMP Education. G.M.B. receives research funding from Istari Oncology, Delcath, Oncosec Medical, Replimmune, and Checkmate Pharmaceuticals. The other authors declare no competing interests.