Paper

The oncometabolite D-2-hydroxyglutarate promotes DNA hypermethylation at lineage-specific enhancers controlling microglial activation in IDHmut gliomas

Iavarone, Antonio, Marijon, Pauline, Alentorn, Agusti, Jouannet, Stephanie, Scuderi, Sarah, Ceccarelli, Michele, Birzu, Cristina, Kaas, Garrett A, Tran, Suzanne, Laurenge, Alice, Pottier, Nina, Fayache, Ines, Mallat, Michel, Quentin, Richard, Mokhtari, Karima, Pugliese, Pietro, Desmons, Aurore, Kingsley, Philip J, Labreche, Karim, Suva, Mario L, Touat, Mehdi, El-Habr, Elias, Duplus, Eric, Marnett, Lawrence J, Hayat, Yvette, Salas, Lucas A, Idbaih, Ahmed, Bielle, Franck, Luis Jaime Castro-Vega, Huillard, Emmanuelle, Sanson, Marc, Verreault, Maite, Mathon, Bertrand

2024

Overview

Tumor-associated macrophages and microglia (TAMs) are highly abundant myeloid cells in gliomas, with their phenotypes and immune responses shaped by ontogeny and microenvironment. TAMs display distinctive transcriptional programs based on the IDH status of tumors, yet the underlying signaling mechanisms remain largely unknown. Herein, we uncover that CD11B+ myeloid cells in human IDH-mutant gliomas exhibit DNA hypermethylation, predominantly at distal enhancers. This hypermethylation impairs the binding of core transcription factors that govern microglial responses, resulting in reduced expression of inflammatory and glycolytic metabolism programs. Prolonged exposure of human primary microglia to D-2-hydroxyglutarate (D-2HG) inhibits TET-mediated demethylation at lineage-specific enhancers, evidenced by elevated 5mC/5hmC ratios near binding motifs. D-2HG-treated microglia showed reduced proinflammatory capacity and enhanced oxidative phosphorylation, consistent with the remodeled enhancer landscape. Conversely, depletion of D-2HG following treatment of a glioma patient with an IDH-mutant inhibitor unleashed microglial reactivity, as assessed by snRNA-seq. Our findings provide a mechanistic rationale for the hyporesponsive state of microglia in IDH-mutant gliomas and support the concept that oncometabolites may disrupt the function of immune cells residing in the tumor microenvironment.Competing Interest StatementL.A.S. is a scientific advisor and co-founder of Cellintec L.L.C., which had no role in this research. M.L.S. is an equity holder, scientific co-founder, and advisory board member of Immunitas Therapeutics. The other authors declare no competing or financial interests.Footnotes* This version of the manuscript has improved formatting

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Brain tumors / Cancer Biology / CD11b antigen / Cell activation / Demethylation / Enhancers / Glioma / Glioma cells / Glycolysis / Immune response / Macrophages / Microglia / Mutants / Myeloid cells / Ontogeny / Oxidative phosphorylation / Phenotypes / Phosphorylation / snRNA / Transcription factors / Tumor microenvironment