Abstract
Glioblastoma (GBM) remains highly resistant to both conventional therapies and immunotherapies due to its ability to suppress antigen presentation and create a lymphocyte-depleted microenvironment within the immune-privileged central nervous system. A key mechanism of immune evasion involves the downregulation of MHC transactivators, NLRC5 (CITA) and CIITA, which are master regulators to express MHC class I and II molecules and the antigen-processing machinery genes. These transactivators (MHC-TA) are normally induced by IFN/TNF-STING signaling but are often genetically or epigenetically silenced in advanced stages. To restore tumor immunogenicity, we developed a novel oncolytic HSV-1 vector with MHC-TA payload. We evaluated its effects across human and murine glioma models, as well as other cancer cell lines. While HSV-1 infection typically suppresses MHC expression, our engineered vector induced upregulation of MHC class II in tumor cells. Interestingly, we also observed MHC upregulation in neighboring, uninfected bystander cells, potentially mediated by extracellular vesicles released from infected cells. Given HSV-1’s intrinsic immune evasion properties, we are also investigating replication-deficient HSV-1 variants to assess the impact of active viral replication on antigen presentation and immune activation. Ongoing in vivo studies in murine GBM models are evaluating the immunological outcomes and therapeutic potential of this strategy. Our findings and ongoing studies support the potential of HSV-1–mediated delivery of exogenous MHC transactivators to reprogram the GBM microenvironment, enhance tumor antigenicity, and improve the efficacy of gene and immunotherapies in GBM.