Abstract LB-218: Protein arginine methyltransferase inhibition of malignant gliomas leads to restored chemokine expression and enhanced immune effector function

Patients with Glioblastoma Multiforme (GBM) face a poor prognosis despite multimodal therapy, thus, there is an unmet need for discovery of novel therapeutic targets and approaches. The immune-privileged nature of the central nervous system and down-modulation of cytokines and chemokines in GBM tumors led us to explore epigenetic approaches to restore expression of immune-relevant genes.PRMT5 is a type II arginine methyltransferase that catalyzes symmetric dimethylation of arginine residues on histone proteins leading to transcriptional repression. Our previous work showed PRMT5 overexpression correlates with poor clinical outcome of GBM patients and that PRMT5 silencing inhibited tumor growth in vitro and in vivo. Microarray transcriptional studies following PRMT5 depletion identified potential PRMT5 target genes interferon-inducible protein 10 (CXCL10) and interferon-inducible T cell α chemoattractant (CXCL11). Increased secretion of CXCL10 and CXCL11 has been shown to facilitate homing of innate and adaptive immune-effector populations that promote anti-GBM activity in vivo. Thus we further investigated the significance of restored CXCL10 and CXLC11 with PRMT5 inhibition in GBM.CXCL10 protein expression was found to be significantly lower in GBM tumors (N = 15) by immunochemistry staining, compared with grade I gliomas (N = 7) (p = 0.0001). PRMT5 knockdown led to increased mRNA and protein expression of CXCL10 and CXCL11. Chromatin immunoprecipitation (ChIP) experiments i...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Immunology Source Type: research