Targeting SEC61 complex to overcome resistance to immunotherapy in GBM

Glioblastoma (GBM) is an incurable brain tumor with a median overall survival of less than 15 months. The recent success of immunotherapy in extracranial malignancies has translated into trials for GBM. Despite its promise, immunotherapy's clinical efficacy has yet to be shown for GBM. The resistance to immunotherapy in GBM is multifactorial. To uncover the targets and pathways contributing to resistance in GBM, we designed and performed an unbiased, genome-wide CRIPR-Cas9 knockout screen screening in a glioma cell line under a cytotoxic T-cell mediated selection pressure. This screen identified SEC61subunit gamma (SEC61G) as a gene involved in immunotherapeutic resistance in GBM. SEC61G is a component of the SEC61 translocon complex in the endoplasmic reticulum. Our data shows that SEC61G is highly expressed in GBM, with genomic amplification seen in up to 30-40% of GBM patients. Knocking out SEC61G sensitized glioma cells to T cell- mediated therapy in vitro. Proteomic analysis of SEC61G knockout cells revealed an interplay of SEC61G expression with the activation of the MAPK pathway in glioma cells. The proposed pre-clinical investigation aims to understand the role SEC61G in immunotherapeutic resistance in GBM and to evaluate SEC61G as a therapeutic target in combination with immunotherapy. We hypothesize that SEC61G confers resistance to T cell-mediated immunotherapy in GBM and that targeting SEC61G can significantly enhance the response of GBM to immunotherapy. This hypothesis will be tested in three Specific Aims. SA1 will investigate how SEC61G overexpression interconnects with the MAPK pathway and contributes to the T cell-mediated therapeutic resistance in glioma cells. SA2 will determine the contribution of SEC61G to the immunosuppressive tumor microenvironment impeding the responses of T cells in GBM. SA3 will investigate SEC61G treatment regimens in combination with T-cell mediated therapies using murine and human models of GBM. Upon completing these studies, we will understand the mechanisms underlying SEC61G-mediated immunotherapeutic resistance, characterize SEC61G as a therapeutic target, and yield translational results for the treatment of GBM and potentially other solid tumors.