Plebanek et al. identified a cDC-derived, CD63+ mature regulatory DC (mregDC) population in mouse TDLNs that potently inhibited cDC cross-presentation and induced Treg formation. mregDCs exhibited unique transcriptional and metabolic signatures associated with the mevalonate (MVA) pathway, including elevated FAO and cellular lipids. Inhibition/KO of the MVA regulator SREBP2 promoted tumor control, improved the TDLN cDC1/mregDC ratio, and increased MHC-I expression by DCs. The presence of lactate in the TME enhanced mregDC abundance in a SREBP2-dependent manner, leading to diminished tumor control.
Contributed by Morgan Janes
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.
Author Info: (1) Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, Duke University, Durham, NC 27708, USA. (2) Department of Medicine, Division of Medical Oncology, D
Author Info: (1) Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, Duke University, Durham, NC 27708, USA. (2) Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, Duke University, Durham, NC 27708, USA. (3) Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, Duke University, Durham, NC 27708, USA. (4) Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, Duke University, Durham, NC 27708, USA. (5) Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27708, USA. (6) Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. (7) Department of Surgery, Division of Surgical Oncology, Duke Cancer Institute, Duke University, Durham, NC 27708, USA. (8) Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, Duke University, Durham, NC 27708, USA. (9) Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, Duke University, Durham, NC 27708, USA. Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27708, USA.
