Abstract 3235: IDH mutant gliomas escape natural killer cell immune surveillance by downregulation of NKG2D ligands

Abstract

Abstract Background: Diffuse gliomas are fatal primary brain tumors that are poorly immunogenic. The basis for insufficient anti-tumor immunity in diffuse gliomas is not understood. Gain of function mutations in isocitrate dehydrogenases (IDH1 and IDH2) promote diffuse glioma formation through epigenetic reprogramming of a number of genes, including immune-related genes. Here, we identify epigenetic dysregulation of natural killer (NK) cell ligand genes as significant contributors to immune escape in glioma. Methods: We analyzed the TCGA database for immune gene expression patterns in IDH mutant or wild-type gliomas and identified differentially expressed immune genes. NKG2D ligands expression levels and NK cell-mediated lysis were measured in IDH mutant and wild-type patient-derived glioma stem cells and in genetically engineered astrocytes. Finally, we assessed the impact of hypomethylating agent 5-aza- 2’deoxycytodine (Decitabine) as a potential NK cell sensitizing agent in IDH mutant cells. Results: All IDH mutant glioma stem-like cell lines exhibited significantly lower expression of NKG2D ligands compared with IDH wild-type cells. Consistent with these findings, IDH mutant glioma cells and astrocytes were resistant to NK cell- mediated lysis. The hypomethylating agent Decitabine increased NKG2D ligand expression, and restored NK-mediated lysis of IDH mutant cells in an NKG2D- dependent manner. Conclusions: IDH mutant glioma cells acquire resistance to NK cells through epigenetic silencing of NKG2D ligands ULBP1 and ULPB3. Decitabine-mediated hypomethylation restores ULBP1 and ULBP3 expression in IDH mutant glioma cells and may provide a clinically useful method to sensitize IDH mutant gliomas to NK cell- mediated immune surveillance in patients with IDH mutated diffuse gliomas. Citation Format: Aparna Rao, Xiaoran Zhang, Christopher Deibert, Paola Sette, Tim Chan, Paola Grandi, Nduka Amankulor. IDH mutant gliomas escape natural killer cell immune surveillance by downregulation of NKG2D ligands. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3235.