Cited by 164Immunotherapy and Immune ResponsesCancer Immunotherapy and BiomarkersImmune cells in cancer

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

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Plebanek, Michael P., Xue, Yue, Nguyen, Y-Van, DeVito, Nicholas C., Wang, Xueying, Holtzhausen, Alisha, Beasley, Georgia M., Theivanthiran, Balamayooran +1 more·2024·Science Immunology

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.

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Authors
Plebanek, M. P., Xue, Y., Nguyen, Y.-V., DeVito, N. C., Wang, X., Holtzhausen, A., Beasley, G. M., Theivanthiran, B., & Hanks, B. A.
Affiliations
  • Duke University (US)
  • University of North Carolina at Chapel Hill (US)
Corresponding author
Hanks, Brent A.
Venue
Science Immunology
Published
2024-05-10
Volume
9
Issue
95
Pages
eadi4191-eadi4191
ISSN
2470-9468 (ISSN-L)
OpenAlex
W4396815136
Cited by
164
References
75
Citations by year
2026: 86 · 2025: 65 · 2024: 13
FWCI
27.43
Type
journal article
Language
en
Open access
Locations
  • Science Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
Funders
  • Damon Runyon Cancer Research Foundation
  • Strong
  • National Institutes of Health
  • National Cancer Institute (R01CA251136, F32CA247067, R37CA249085, P30CA016086, P30CA014236)
  • Duke Cancer Institute
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
Keywords
lactate, SREBP2, regulatory dendritic cells, dendritic cell maturation, tumor microenvironment, melanoma, CD63, mevalonate biosynthesis, Th2 cells, regulatory T cells, antitumor immunity, sentinel lymph node, immunometabolism, cancer immunotherapy
MeSH terms
Animals, Dendritic Cells, Female, Humans, Immune Tolerance, Melanoma, Melanoma, Experimental, Mice, Inbred C57BL, Signal Transduction, Disease Progression, Lactic Acid, Cell Line, Tumor, Mice, Sterol Regulatory Element Binding Protein 2, Tumor Microenvironment

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