Mutant IDH1 promotes phagocytic function of microglia/macrophages in gliomas by downregulating ICAM1.

Abstract

Tumor-associated microglia/macrophages (TAMs) are the main innate immune effector cells in malignant gliomas and have both pro- and anti-tumor functions. The plasticity of TAMs is partially dictated by oncogenic mutations in tumor cells. Heterozygous IDH1 mutation is a cancer driver gene prevalent in grade II/III gliomas, and IDH1 mutant gliomas have relatively favorable clinical outcomes. It is largely unknown how IDH mutation alters TAM phenotypes to influence glioma growth. Here we established clinically relevant isogenic glioma models carrying monoallelic IDH1 R132H mutation (IDH1R132H/WT) and found that IDH1R132H/WT significantly downregulated immune response-related pathways in glioma cells, indicating an immunomodulation role of mutant IDH1. Co-culturing IDH1R132H/WT glioma cells with human macrophages promoted anti-tumor phenotypes of macrophages and increased macrophage migration and phagocytic capacity. In orthotopic xenografts, IDH1R132H/WT decreased tumor growth and prolonged animal survival, accompanied by increased TAM recruitment and upregulated phagocytosis markers, suggesting the induction of anti-tumor TAM functions. Using human cytokine arrays that query 36 proteins, we identified significant downregulation of ICAM-1/CD54 in IDH1R132H/WT gliomas, which was further confirmed by ELISA and immunoblotting analyses. ICAM1 gain-of-function studies revealed that ICAM1 downregulation in IDH1R132H/WT cells played a mechanistic role to mediate the immunomodulation function of IDH1R132H/WT. ICAM-1 silencing in IDH1 wild-type glioma cells decreased tumor growth and increased the anti-tumor function of TAMs. Together, our studies support a new TAM-mediated phagocytic function within IDH1 mutant gliomas, and improved understanding of this process may uncover novel approaches to targeting IDH1 wild type gliomas.

• Authors: Ding Ma, Daqian Zhan, Yi Fu, Shuang Wei, Bachchu Lal, Jie Wang, Yunqing Li, Hernando Lopez-Bertoni, Fatih Yalcin, Omar Dzaye, Charles G Eberhart, John Laterra, Mary Ann Wilson, Mingyao Ying, Shuli Xia
• Journal: Cancer letters (Cancer Lett) Vol. 517 Pg. 35-45 (10 01 2021) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 34098063 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• ICAM1 protein, human
• Intercellular Adhesion Molecule-1
• Isocitrate Dehydrogenase
• IDH1 protein, human

Topics

• Animals
• Cell Line
• Cell Line, Tumor
• Down-Regulation (genetics)
• Female
• Glioma (genetics)
• Humans
• Intercellular Adhesion Molecule-1 (genetics, metabolism)
• Isocitrate Dehydrogenase (genetics)
• Leukocytes, Mononuclear
• Macrophages (metabolism)
• Mice
• Mice, SCID
• Microglia (metabolism)
• Mutation (genetics)
• THP-1 Cells