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

Publication ,  Journal Article
Plebanek, MP; Xue, Y; Nguyen, Y-V; DeVito, NC; Wang, X; Holtzhausen, A; Beasley, GM; Theivanthiran, B; Hanks, BA
Published in: Sci Immunol
May 10, 2024

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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Published In

Sci Immunol

DOI

EISSN

2470-9468

Publication Date

May 10, 2024

Volume

9

Issue

95

Start / End Page

eadi4191

Location

United States

Related Subject Headings

  • Tumor Microenvironment
  • Sterol Regulatory Element Binding Protein 2
  • Signal Transduction
  • Mice, Inbred C57BL
  • Mice
  • Melanoma, Experimental
  • Melanoma
  • Lactic Acid
  • Immune Tolerance
  • Humans
 

Citation

APA
Chicago
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Plebanek, M. P., Xue, Y., Nguyen, Y.-V., DeVito, N. C., Wang, X., Holtzhausen, A., … Hanks, B. A. (2024). A lactate-SREBP2 signaling axis drives tolerogenic dendritic cell maturation and promotes cancer progression. Sci Immunol, 9(95), eadi4191. https://doi.org/10.1126/sciimmunol.adi4191
Plebanek, Michael P., Yue Xue, Y-Van Nguyen, Nicholas C. DeVito, Xueying Wang, Alisha Holtzhausen, Georgia M. Beasley, Balamayooran Theivanthiran, and Brent A. Hanks. “A lactate-SREBP2 signaling axis drives tolerogenic dendritic cell maturation and promotes cancer progression.Sci Immunol 9, no. 95 (May 10, 2024): eadi4191. https://doi.org/10.1126/sciimmunol.adi4191.
Plebanek MP, Xue Y, Nguyen Y-V, DeVito NC, Wang X, Holtzhausen A, et al. A lactate-SREBP2 signaling axis drives tolerogenic dendritic cell maturation and promotes cancer progression. Sci Immunol. 2024 May 10;9(95):eadi4191.
Plebanek, Michael P., et al. “A lactate-SREBP2 signaling axis drives tolerogenic dendritic cell maturation and promotes cancer progression.Sci Immunol, vol. 9, no. 95, May 2024, p. eadi4191. Pubmed, doi:10.1126/sciimmunol.adi4191.
Plebanek MP, Xue Y, Nguyen Y-V, DeVito NC, Wang X, Holtzhausen A, Beasley GM, Theivanthiran B, Hanks BA. A lactate-SREBP2 signaling axis drives tolerogenic dendritic cell maturation and promotes cancer progression. Sci Immunol. 2024 May 10;9(95):eadi4191.

Published In

Sci Immunol

DOI

EISSN

2470-9468

Publication Date

May 10, 2024

Volume

9

Issue

95

Start / End Page

eadi4191

Location

United States

Related Subject Headings

  • Tumor Microenvironment
  • Sterol Regulatory Element Binding Protein 2
  • Signal Transduction
  • Mice, Inbred C57BL
  • Mice
  • Melanoma, Experimental
  • Melanoma
  • Lactic Acid
  • Immune Tolerance
  • Humans