IMMU-37. Exploring the immunosuppressive role of Human Endogenous Retrovirus K in the glioblastoma microenvironment

Abstract Glioblastoma (GBM) is the most lethal primary brain tumor with a five-year survival rate below 5%. Its tumor microenvironment (TME) is highly immunosuppressive, conferring resistance to immunotherapies that have successfully treated other malignancies. We uncovered robust overexpression of Human Endogenous Retrovirus K (HERV-K) in GBM that is associated with poor patient survival. HERVs are remnants of ancient germline retroviral infections comprising approximately 8% of the human genome and are typically transcriptionally silenced. However, in cancer, aberrant expression of HERV genes, such as env (envelope), may occur. Given prior evidence that retroviral Env proteins are immunosuppressive, we investigated HERV-K Env’s role in the GBM TME. Analysis of bulk RNA sequencing data from 71 GBM patients demonstrated that high HERV-K Env expression is associated with low immune cell infiltration in tumors and worse prognosis. In addition, this relationship is maintained in a published spatial transcriptomic dataset, which shows an inverse correlation between T cell infiltration and HERV-K Env expression. In vitro assays show that recombinant HERV-K Env binds T cells, inhibits CD4+ and CD8+ T cell proliferation, modulates T cell activation and immune checkpoint expression, and suppresses IL-10 secretion. These findings support HERV-K as a functional immunosuppressive factor in GBM. To further define HERV-K Env’s role in the GBM TME, we are leveraging orthotopic GBM mouse models and bioinformatic analyses, such as scRNAseq and spatial transcriptomics of patient tumors (n=43 tumor cores from 11 patients). Early data from orthotopic models shows differential T-cell phenotypes between control and HERV-K Env-overexpressing tumors. Altogether, our study uncovers a retroviral protein with direct immunosuppressive effects in GBM, providing insights into mechanisms of immunosuppression in the GBM TME and offering a potential therapeutic target. Targeting HERV-K Env in GBM may help enhance antitumor immunity and improve patient outcomes in this otherwise treatment-refractory disease.