A lactate-SREBP2 signaling axis drives tolerogenic dendritic cell maturation and promotes cancer progression
Open accessAbstract
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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The S100hiHLAlo cDC2 cluster expresses genes that are known markers of mature regulatory DCs (mregDCs), a cell type previously reported to support Treg cell function.
“which are markers of mature regulatory DCs (mregDCs) shown to promote Treg cell function30 (Fig. 4e).”
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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.
- ORCID
- Venue
- Science Immunology
- Published
- 2024-05-10
- Volume
- 9
- Issue
- 95
- Pages
- eadi4191-eadi4191
- ISSN
- 2470-9468 (ISSN-L)
- PMC
- PMC11926670
- 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
- green
- www.ncbi.nlm.nih.gov
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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