We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
A lactate-SREBP2 signaling axis drives tolerogenic dendritic cell maturation and promotes cancer progression.
- Authors
Plebanek, Michael P.; Xue, Yue; Nguyen, Y-Van; DeVito, Nicholas C.; Wang, Xueying; Holtzhausen, Alisha; Beasley, Georgia M.; Theivanthiran, Balamayooran; Hanks, Brent A.
- Abstract
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 of CD63 as a specific surface marker, we demonstrate that mature regulatory DCs (mregDCs) migrate to tumor-draining lymph node tissues and suppress DC antigen cross-presentation in trans while promoting T helper 2 and regulatory T cell differentiation. Transcriptional and metabolic studies showed that mregDC functionality is dependent on the mevalonate biosynthetic pathway and its master transcription factor, SREBP2. We found that melanoma-derived lactate activates SREBP2 in tumor DCs and drives conventional DC transformation into mregDCs via homeostatic or tolerogenic maturation. DC-specific genetic silencing and pharmacologic inhibition of SREBP2 promoted antitumor CD8+ T cell activation and suppressed melanoma progression. CD63+ mregDCs were found to reside within the lymph nodes of several preclinical tumor models and in the sentinel lymph nodes of patients with melanoma. Collectively, this work suggests that a tumor lactate-stimulated SREBP2-dependent program promotes CD63+ mregDC development and function while serving as a promising therapeutic target for overcoming immune tolerance in the TME. Editor's summary: Dendritic cells (DCs) are critical for generating antitumor adaptive immune responses but can become dysfunctional in the tumor microenvironment. Using mouse models of melanoma and sentinel lymph node samples from patients with melanoma, Plebanek et al. found that mature DCs enriched in immunoregulatory molecules (mregDCs) express high levels of genes regulating cholesterol synthesis and the cell surface marker CD63. CD63+ mregDCs suppressed antitumoral T cell responses, which could be prevented by genetic or pharmacological targeting of sterol regulatory element–binding protein 2 (SREBP2). Tumor-derived lactate promoted the development of SREBP2-dependent mregDCs. These findings demonstrate that targeting cholesterol metabolism and/or tumor lactate production may be a promising approach to alleviate DC-driven tumor immunosuppression. —Claire Olingy
- Subjects
LACTATES; DENDRITIC cells; STEROL regulatory element-binding proteins; REGULATORY T cells; SENTINEL lymph nodes; T cell differentiation; MELANOMA
- Publication
Science Immunology, 2024, Vol 9, Issue 95, p1
- ISSN
2470-9468
- Publication type
Article
- DOI
10.1126/sciimmunol.adi4191