TMIC-76. PRMT5 MODULATES T CELL PROLIFERATION IN GLIOBLASTOMA TUMOR MICROENVIRONMENT

Abstract INTRODUCTION Glioblastoma, the most common malignant brain tumor, presents a significant obstacle because of its immunosuppressive tumor microenvironment, complicating standard treatment approaches. Protein Arginine Methyltransferase 5 (PRMT5) that regulates cellular functions by symmetrically dimethylating arginine residues is dysregulated in glioblastoma. Inhibiting PRMT5 induces apoptosis and senescence in the differentiated and undifferentiated glioblastoma tumor cells respectively. As PRMT5 is known to play an important role in immune cell response and T cell reprogramming, in this study we sought to probe the role of PRMT5 in the modulation of glioblastoma tumor immune response. METHODS We inhibited PRMT5 using small molecule inhibitor (LLY283) or PRMT5 target specific siRNA in patient-derived primary GBM neurospheres (GBMNS) and assessed the T-cell proliferation and MDSC induction by flow cytometry. Further, we also probed for PDL-1 and IL-6 expression by ELISA and westernblot assays. RESULT: PRMT5 inhibition significantly increased CD4+ T-cell proliferation but the MDSC induction was suppressed. As PDL-1/IL-6 axis is known to play a significant role in both anti-tumorigenic T-cell proliferation and pro-tumorigenic MDSC induction, we probed for the expression of PDL-1 and IL-6. While PRMT5 blockade reduced PDL-1 expression, IL-6 expression was upregulated. CONCLUSION Our results suggests that PRMT5 inhibition increases T-cell proliferation potentially by blocking MDSC induction. Further studies are underway to understand the nexus between PDL-1/IL-6 and modulation of MDSC/T-cell activation in the context of PRMT5 status in glioblastoma and their potential impact on the anti-tumorigenic effect in an in vivo GBM model.