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Tumor Rapid Fire Abstract

Tumor

Epigenetic potentiation of anti-tumor immune responses using viral mimicry for gliomas

Sunday, May 5, 2024
1:49 PM – 1:51 PM CT
Location:  S405a
Disclosure(s):
Jay Chandar: No financial relationships to disclose
Introduction: Clinical trials using immune checkpoint inhibition(ICI) have traditionally failed in glioblastoma(GBM). Recently, our lab and others have suggested that viral mimicry may improve the efficacy of ICI in various solid tumors. Viral mimicry refers to epigenetic activation of Human Endogenous Retroviruses(HERVs) and their resultant anti-tumor immune responses. HERVs are epigenetically silenced via master regulator, np220, and H3K9me3 methylation. Removal of these repressive modifications has been associated with a robust anti-viral immune response.

Methods: We seek to decipher the role of viral-mimicry in potentiating ICI through epigenetic reprogramming(NP220) in gliomas.

Results: Primarily, we demonstrate that HERV expression among 48 superfamilies is inversely correlated to NP220 expression in gliomas using a tailored bulk transcriptional dataset from 71 newly-diagnosed GBMs. In addition, 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). To confirm these in-silico findings, we further demonstrate that NP220 knockdown induces intracellular HERV mediated dsRNA-signaling cascades via RIG-1 and TLR3. NP220 knockdown exponentially increases PD-L1 checkpoint expression(p value: < 0.001), downregulates H3K9 trimethylation, and increases cytoplasmic accumulation of cellular endogenous dsRNA in established human and mouse glioma cell lines. This response was recapitulated in recurrent GBM samples with radiographic responses to ICI(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 demonstrate that np220 is linked to reduced immune cell infiltration(CD8, DCs) in the glioma microenvironment through RNA deconvolution(RCD8=-.202, RDC=-0.198)(pCD8=8.79E-06, pDC=1.34E-05). This relationship was maintained in syngeneic immunocompetent mice where NP220 KO upregulates PD-L1 expression (p < 0.0001) and dsRNA-signaling cascade(RIG-1, TLR3, NFβ). Importantly, we showed that NP220 KO mice treated with a PD-L1 inhibitor had significantly improved long-term survival(mOS >50 days, p< 0.0001) and tumor volume(p < 0.0001) relative to all other groups. This survival benefit was correlated to downregulation of IL-6(p < 0.0001) and TNF-α(p < 0.0001) and upregulation of IFN-γ(p < 0.0001).

Conclusion : Our findings suggest np220 could serve as an epigenetic target to potentiate immunotherapy in gliomas.