Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Lactate reprograms glioblastoma immunity through CBX3-regulated histone lactylation
Shuai Wang, … , Dimitris G. Placantonakis, Jeremy N. Rich
Shuai Wang, … , Dimitris G. Placantonakis, Jeremy N. Rich
Published November 15, 2024
Citation Information: J Clin Invest. 2024;134(22):e176851. https://doi.org/10.1172/JCI176851.
View: Text | PDF
Research Article Metabolism Oncology

Lactate reprograms glioblastoma immunity through CBX3-regulated histone lactylation

  • Text
  • PDF
Abstract

Glioblastoma (GBM), an aggressive brain malignancy with a cellular hierarchy dominated by GBM stem cells (GSCs), evades antitumor immunity through mechanisms that remain incompletely understood. Like most cancers, GBMs undergo metabolic reprogramming toward glycolysis to generate lactate. Here, we show that lactate production by patient-derived GSCs and microglia/macrophages induces tumor cell epigenetic reprogramming through histone lactylation, an activating modification that leads to immunosuppressive transcriptional programs and suppression of phagocytosis via transcriptional upregulation of CD47, a “don’t eat me” signal, in GBM cells. Leveraging these findings, pharmacologic targeting of lactate production augments efficacy of anti-CD47 therapy. Mechanistically, lactylated histone interacts with the heterochromatin component chromobox protein homolog 3 (CBX3). Although CBX3 does not possess direct lactyltransferase activity, CBX3 binds histone acetyltransferase (HAT) EP300 to induce increased EP300 substrate specificity toward lactyl-CoA and a transcriptional shift toward an immunosuppressive cytokine profile. Targeting CBX3 inhibits tumor growth by both tumor cell–intrinsic mechanisms and increased tumor cell phagocytosis. Collectively, these results suggest that lactate mediates metabolism-induced epigenetic reprogramming in GBM that contributes to CD47-dependent immune evasion, which can be leveraged to augment efficacy of immuno-oncology therapies.

Authors

Shuai Wang, Tengfei Huang, Qiulian Wu, Huairui Yuan, Xujia Wu, Fanen Yuan, Tingting Duan, Suchet Taori, Yingming Zhao, Nathaniel W. Snyder, Dimitris G. Placantonakis, Jeremy N. Rich

×

Figure 5

Histone lactylation regulates immune evasion pathways in GBM cells.

Options: View larger image (or click on image) Download as PowerPoint
Histone lactylation regulates immune evasion pathways in GBM cells.
(A) ...
(A) Western blot of CD47, phosphorylated STAT3 (p-STAT3), STAT3, and Kla protein levels in GSC23 and CW468 treated with different concentrations of NaLac. Histone 3 and Tubulin were used as loading controls. (B) Quantification of effect of NaLac on membrane CD47 expression by flow cytometry (representative data shown in Supplemental Figure 3C) (n = 3/group; 1-way ANOVA; F[2, 6] = 12.36 for GSC23), (F[2, 6] = 8.913 for CW468). (C) Western blot of CD47, p-STAT3, STAT3, and Kla protein levels in GSC23 and CW468 treated with different concentrations of DCA. Histone 3 and Tubulin were used as loading controls. (D) Quantification of effect of DCA on membrane CD47 expression by flow cytometry (representative data shown in Supplemental Figure 3D) (n = 3/group; 1-way ANOVA; F[2, 6] = 54.92 for GSC23), F[2, 6] = 53.89 for CW468). (E–G) GSEA analysis shows that lactate stimulation was negatively related to IFN-γ response, IFN-α response, and glycolysis. (H) Representative bioluminescent images on days 7 and 21 of immunocompetent mice implanted with CT2A murine glioma cells. Tumor-bearing mice were treated with either PBS plus IgG (100 μg/mouse), PBS plus anti-CD47-Ab (100 μg/mouse), DCA (150 mg/kg/d) plus IgG (100 μg/mouse), or DCA (150 mg/kg/d) plus anti-CD47-Ab (100 μg/mouse) on days 7 and 14. (I) Quantification of bioluminescent signals in CT2A tumor-bearing mice on days 7 and 21 (n = 5/group; 2-way ANOVA; F[3, 32] = 23.15). (J) Kaplan-Meier survival curves of tumor-bearing mice implanted with CT2A cells treated with vehicle control, vehicle control (PBS) plus IgG, PBS plus anti-CD47-Ab, DCA plus IgG, or DCA plus anti-CD47-Ab (n = 5/group; log-rank tests). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts