383 Epigenetic Potentiation of Anti-tumor Immune Responses Using Viral Mimicry for Gliomas

INTRODUCTION: Human endogenous retroviruses (HERVs) account for approximately 8% of our genome and are evolutionary relics of a germline retroviral infection. Although normally silenced by a master epigenetic regulator, np220, HERVs may be re-expressed in cellular states with marked epigenetic dysregulation and induce innate anti-viral inflammatory responses. This viral mimicry immune response sensitizes tumors to immunotherapy by eliciting double-stranded RNAs (dsRNA)-mediated interferon signaling cascades. Hence, viral mimicry could serve as a predictor of clinical responses to immunotherapy. METHODS: We conducted a preclinical study on the role of np220 in GBM and mediating viral mimicry responses. RESULTS: Using a tailored bulk transcriptional dataset from 71 newly diagnosed high-grade GBMs, we demonstrated significantly negative correlations between np220 expression and 48 HERV superfamilies. Additionally, using a transcriptional deconvolution pipeline of low-and high-grade gliomas, we demonstrated that np220 is negatively correlated with innate antiviral immune response signatures (TLR3) (RTLR3 = -0.300, pTLR3 = 0.00006). Our in vitro studies have shown that NP220 knockdown induces intracellular HERV-mediated dsRNA-signaling cascades via RIG-1 and TLR3. NP220 knockdown exponentially increases PD-L1 expression (p-value: <0.001), and, increases cytoplasmic accumulation of cellular endogenous dsRNA in established human and mouse glioma cell lines which may induce the interferon-mediated response. This response was recapitulated in recurrent GBM samples with radiographic responses to checkpoint inhibition (anti-PD1) with widely increased expression of dsRNA, PD-L1 and perivascular CD8 cell infiltration, suggesting dsRNA-signaling may mediate response to immunotherapy. Furthermore, we showed np220 is linked to reduced immune cell infiltration (CD8, Dendritic Cells) in the glioma microenvironment through deconvolution of RNA-seq data from TCGA (RCD8 = -.202, RDC = -0.198) (pCD8 = 8.79E-06, pDC = 1.34E-05). CONCLUSIONS: Our findings suggest that np220 could serve as a target to potentiate glioma ICI for immune response.