Mutant IDH1 promotes phagocytic function of microglia/macrophages in gliomas by downregulating ICAM1. (1st October 2021)

• Record Type: Journal Article
• Authors: Ma, Ding; Zhan, Daqian; Fu, Yi; Wei, Shuang; Lal, Bachchu; Wang, Jie; Li, Yunqing; Lopez-Bertoni, Hernando; Yalcin, Fatih; Dzaye, Omar; Eberhart, Charles G.; Laterra, John; Wilson, Mary Ann; Ying, Mingyao; Xia, Shuli
• Is Part Of: Cancer letters. Volume 517(2021)
• Page Start: 35
• Page End: 45
• Publication Date: 2021-10-01
• Subjects: Monoallelic IDH1 R132H mutation -- Single base editing -- Glioma-infiltrating microglia/macrophages -- CD107a -- Phagocytosis -- ICAM1; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2021.05.038
• Languages: English
• ISSNs: 0304-3835

Abstract

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 (IDH1 R132H/WT ) and found that IDH1 R132H/WT significantly downregulated immune response-related pathways in glioma cells, indicating an immunomodulation role of mutant IDH1. Co-culturing IDH1 R132H/WT glioma cells with human macrophages promoted anti-tumor phenotypes of macrophages and increased macrophage migration and phagocytic capacity. In orthotopic xenografts, IDH1 R132H/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 IDH1 R132H/WT gliomas, which was further confirmed by ELISA and immunoblotting analyses. ICAM1 gain-of-function studies revealed that ICAM1 downregulation in IDH1 R132H/WT cells played a mechanistic role to mediate the immunomodulation function of IDH1 R132H/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. Highlights: Mutant IDH1 in glioma cells elicits an immunomodulation role by promoting M1 polarization of macrophages in co-cultures. IDH1 mutant glioma cells decrease tumor growth and prolong animal survival, accompanied by increased recruitment of TAMs. We identified significant downregulation of ICAM-1/CD54 in gliomas carrying IDH1 R132H/WT using human cytokine arrays. ICAM1 downregulation in IDH1 R132H/WT glioma cells played a mechanistic role in mediating mutant IDH1's function.