Advances in Immune Microenvironment and Immunotherapy of Isocitrate Dehydrogenase Mutated Glioma

Abstract

The tumor immune microenvironment and immunotherapy have become current important tumor research concerns. The unique immune microenvironment plays a crucial role in the malignant progression of isocitrate dehydrogenase (IDH) mutant gliomas. IDH mutations in glioma can inhibit tumor-associated immune system evasion of NK cell immune surveillance. Meanwhile, mutant IDH can inhibit classical and alternative complement pathways and directly inhibit T-cell responses by metabolizing isocitrate to D-2-Hydroxyglutaric acid (2-HG). IDH has shown clinically relevant efficacy as a potential target for immunotherapy. This article intends to summarize the research progress in the immunosuppressive microenvironment and immunotherapy of IDH-mutant glioma in recent years in an attempt to provide new ideas for the study of occurrence, progression, and treatment of IDH-mutant glioma.

Keywords: dehydrogenase; glioma; immunotherapy; isocitrate; tumor microenvironment.

Figure 1

An IDH1 mutation lowers the expression of CCL-2, CXCL-2, and C5a, which reduces immune cell recruitment and chemotaxis, thus inhibiting the tumor-associated immune system. IDH mutations cause hypermethylation of the ULBP1 and ULBP3 promoters, as well as a decrease in NKG2DL, which affects NKG2DL-NKG2D interaction, inhibits NK cell activation, and ultimately escapes immune surveillance by NK cells. 2-HG can activate NF-κB, regulate CX3CL1 expression, and then CX3CL1 recruit NK cells to the tumor location.

Figure 2

Isocitrate is metabolized to 2-hydroxyglutarate by mutant IDH, and 2-HG reduces C3 deposition on cells in a dose-dependent manner. In addition, it inhibits C3b (iC3b) opsonization and complement-mediated phagocytosis, and complement activation assembly of C5 convertases in the classical pathway, thereby inhibiting MAC-mediated tumor cell damage. 2-Hg inhibited the protein expression level of STAT1, thus decreasing chemokines related to type 1 (such as CXCL10), and affecting the aggregation of CD8+ T cells. in addition, it also directly inhibited the proliferation and cytokine production of CD4+ and CD8+ T cells, activated Th1, Th17, and Treg in tumors, and inhibited IFN-γ production by activating T cells in a dose-dependent manner, thereby inhibiting T cell migration.

Figure 3

Administration of peptide vaccine IDH1 (R132H) induced specific therapeutic T-helper cell responses and mutation-specific antibodies. After mIDH1 peptide injection, the immune system can effectively target R132H mutation and modify the tumor microenvironment by increasing the number of peripheral CD8+ T cells, IFN-γ production and anti-IDH1 mutant antibodies, up-regulating intratumoral IFN- γ, granzyme-b, and perforin-1, and downregulating TGF-β2 and IL-10, thereby significantly prolonging survival of the mice. IDH-C35 reduces ULBP1, ULBP3, and PD-L1 DNA methylation levels and restores STAT1 to reverse CXCL10 and T cell accumulation.