A lactate-SREBP2 signaling axis drives tolerogenic dendritic cell maturation and promotes cancer progression

• DOI: 10.1126/sciimmunol.adi4191
• Publication Date: 2024-05-10T17:58:15Z
• Authors: Michael P. Plebanek; Yue Xue; Y-Van Nguyen; Nicholas C. DeVito; Xueying Wang; Alisha Holtzhausen; Georgia M. Beasley; Balamayooran Thei...; Brent A. Hanks
• Keywords: Cross-Presentation; Cancer Immunotherapy; Tumor progression

Conventional dendritic cells (DCs) are essential mediators of antitumor immunity. As a result, cancers have developed poorly understood mechanisms to render DCs dysfunctional within the tumor microenvironment (TME). After identification CD63 as specific surface marker, we demonstrate that mature regulatory (mregDCs) migrate tumor-draining lymph node tissues and suppress DC antigen cross-presentation in trans while promoting T helper 2 cell differentiation. Transcriptional metabolic studies showed mregDC functionality is dependent on mevalonate biosynthetic pathway its master transcription factor, SREBP2. We found melanoma-derived lactate activates SREBP2 drives conventional transformation into mregDCs via homeostatic or tolerogenic maturation. DC-specific genetic silencing pharmacologic inhibition promoted CD8 + activation suppressed melanoma progression. were reside nodes several preclinical models sentinel patients with melanoma. Collectively, this work suggests lactate-stimulated SREBP2-dependent program promotes development function serving promising therapeutic target for overcoming immune tolerance TME.