Abstract

Abstract Glioblastoma (GBM) remains to be one of the deadliest cancers with poor prognosis and limited treatment options. While immunotherapies have revolutionized the field for other cancers, GBM remains resistant to these types of interventions partly due to its highly immunosuppressive tumor microenvironment, which is characterized by accumulation of exhausted CD8+ T cells. Therefore, there is a pressing need to identify molecular targets for improve anti-tumorigenic T cell response. Previous studies in our laboratory identified dipeptidyl peptidase-4 (DPP-4), an exopeptidase and a membrane-bound signaling receptor, as a potential marker of immunosuppression in GBM. While DPP-4 is well-drugged due to its role in insulin metabolism, the function of DPP-4 in immune regulation and cancer remains poorly defined. I observed that DPP-4 is highly expressed by CD8+ T cells GBM patients and preclinical models. Furthermore, DPP-4 levels increased with the exhaustion or memory differentiation of effector T cell. Pharmaceutical inhibition of DPP-4 enriched expression of genes related to lymphocyte activation and mitochondrial metabolism. These transcriptional changes were accompanied by enhanced T cell proliferation, cytotoxic function, and effector mediator production under exhaustion conditions. These findings suggest that pharmacological inhibition of DPP-4 promotes anti-tumorigenic function of CD8+ T-cell by preventing exhaustion and support future translational efforts to repurpose DPP-4 inhibitors as immunotherapy agents in GBM, given their favorable safety profiles.