◥Purpose: Extracellular matrix (ECM) component hyaluronan (HA) facilitates malignant phenotypes of glioblastoma (GBM), however, whether HA impacts response to GBM immunotherapies is not known. Herein, we investigated whether degradation of HA enhances oncolytic virus immunotherapy for GBM.Experimental Design: Presence of HA was examined in patient and murine GBM. Hyaluronidase-expressing oncolytic adenovirus, ICOVIR17, and its parental virus, ICOVIR15, without transgene, were tested to determine if they increased animal survival and modulated the immune tumor microenvironment (TME) in orthotopic GBM. HA regulation of NF-kB signaling was examined in virus-infected murine macrophages. We combined ICOVIR17 with PD-1 checkpoint blockade and assessed efficacy and determined mechanistic contributions of tumorinfiltrating myeloid and T cells.Results: Treatment of murine orthotopic GBM with ICOVIR17 increased tumor-infiltrating CD8 þ T cells and macrophages, and upregulated PD-L1 on GBM cells and macrophages, leading to prolonged animal survival, compared with control virus ICOVIR15. High molecular weight HA inhibits adenovirus-induced NF-kB signaling in macrophages in vitro, linking HA degradation to macrophage activation. Combining ICOVIR17 with anti-PD-1 antibody further extended the survival of GBM-bearing mice, achieving long-term remission in some animals. Mechanistically, CD4 þ T cells, CD8 þ T cells, and macrophages all contributed to the combination therapy that induced tumor-associated proinflammatory macrophages and tumor-specific T-cell cytotoxicity locally and systemically.Conclusions: Our studies are the first to show that immune modulatory ICOVIR17 has a dual role of mediating degradation of HA within GBM ECM and subsequently modifying the immune landscape of the TME, and offers a mechanistic combination immunotherapy with PD-L1/PD-1 blockade that remodels innate and adaptive immune cells.

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IDH1/2-mutant gliomas are primary brain tumors for which curative treatments are lacking. Using a chemical screen targeting chromatin modifiers, we identified the histone H3 K27me3 demethylase inhibitor GSK-J4 and class I histone deacetylase inhibitors such as Belinostat as potent, genotype-selective agents against IDH1-mutant glioma. RNA-sequencing on paired wild-type and IDH1R132H cells revealed induction of stress-related pathways in IDH1R132H cells, which was dependent on the onco-metabolite 2-hydroxyglutarate (2-HG). GSK-J4 and Belinostat combination activated an ATF4-mediated integrated stress response, cell cycle arrest, and DDIT3/CHOP-dependent apoptosis in IDH1-mutant cells. We show that genetic ablation of GSK-J4 target histone demethylases, KDM6A and KDM6B phenocopied the pharmacological effects of the compound. Combination treatment of GSK-J4 and Belinostat extended animal survival in an IDH1-mutant orthotopic model in vivo. These results provide a possible therapeutic approach that exploits epigenetic vulnerabilities of IDH-mutant gliomas.Statement of SignificanceIDH1/2 genes are frequently mutated in low grade glioma and secondary glioblastoma. These tumors exhibit a distinct epigenome with increased DNA and histone methylation; therefore, identifying and exploiting their epigenetic vulnerabilities may lead to effective therapies. We discover targeting of KDM6A/6B together with HDACs provides a promising genotype-specific therapeutic approach.

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