IMST-14. IDH1 R132H MUTATION INHIBITS ANTI-GLIOMA IMMUNE RESPONSES THROUGH POST-TRANSCRIPTIONAL DOWN-REGULATION OF STAT1 AND TYPE-1 CHEMOKINES

Abstract

We evaluated whether isocitrate dehydrogenase (IDH) mutations could directly alter the immune landscape of gliomas, possibly through production of the onco-metabolite, 2-hydroxygluterate (2HG). TCGA RNAseq data demonstrate reduced expression of CD8 T-cell, type-1 effector and chemokine genes in IDH-mutated (Mut) patients compared to IDH-wild-type (Wt) cases. Conversely, we observed no differences in B-cell, type-2 or regulatory T-cell-related genes between IDH-Wt and IDH-Mut cases. Normal human astrocyte (NHA) cells and syngeneic GL261 glioma models expressing the R132H mutated IDH1 (NHA-Mut and GL261-Mut, respectively) further demonstrated that the IDH1 mutation and 2HG directly reduce CXCL10 protein and migration of T-cells to the tumor site, which was reversed by an IDH-specific inhibitor, IDH-C35. Further, while mice receiving prophylactic peptide vaccination targeting glioma-associated antigens resulted in clearance of GL261-Wt tumors, vaccinated mice could not reject GL261-Mut tumors. Treatment of vaccinated mice bearing GL261-Mut tumors with IDH-C35 enhanced anti-tumor immunity and prolonged survival compared to mice receiving vaccine alone. Interestingly, both parental GL261 cells treated with 2HG and GL261-Mut cells demonstrated decreased amounts of STAT1 protein but not mRNA compared with untreated GL261-Wt cells, suggesting that STAT1, a known regulator of CXCL10, is regulated at the post-transcriptional level in IDH-Mut gliomas. Consistent with these findings, TCGA microRNA data demonstrated increased levels of miR-145, a known regulator of STAT1, in IDH-Mut compared with IDH-Wt cases. We next evaluated direct tumor extrinsic implications of the IDH1 mutation. 2HG, which is known to be present in the tumor microenvironment, directly induced a ~10 fold increase in miR-145-5p and reduced both STAT1 levels and CXCL10 secretion from primary and BV2 murine microglia. Our findings demonstrate both glioma-intrinsic and extrinsic mechanisms of immunosuppression in IDH-Mut gliomas and suggest that IDH inhibitors can be used to enhance T-cell migration to the tumor site in patients with IDH-Mut tumors.