NF-kB Inducing Kinase (NIK) Drives Metabolic Reprogramming of Myeloid Cells in Immunity and Cancer

Abstract

Myeloid cells, part of the innate immune system, are front line host defense cells that play critical roles in inflammation and tissue repair. This functional plasticity is driven by metabolic changes that occur during activation and is hijacked in disease states, such as cancer. Glioblastoma multiforme (GBM) is the deadliest neurological tumor with bleak survival statistics. Unlike other tumors, new therapeutics have not been successfully developed against Glioblastoma due to factors such as the blood brain barrier, late-stage diagnosis, severe immunosuppression, and an extremely invasive phenotype. Recent work has shown that NF-κB Inducing Kinase (NIK) can be a potential therapeutic target against GBM due to multiple tumor intrinsic roles of NIK but the full extent of tumor extrinsic roles of NIK remains unknown. This dissertation investigates the role of NIK in myeloid cells as macrophages and microglia are known to compromise up to 50% of the mass of GBM tumors and play critical roles in immune recruitment and modulation in the tumor microenvironment (TME). Both NIK deficient (NIK^KO) macrophages and microglia have altered metabolic profiles consisting of decreased oxidative metabolism, which prevents the proper activation of a pro-repair/pro-tumor phenotype by decreasing typical pro-repair gene expression and functional readouts such as cellular adhesion and migration. Loss of NIK in the TME confers a survival benefit driven mainly by a conditional loss of NIK in microglia (NIK^cKO), as opposed to macrophages, with a sex specific survival increase observed in NIK^cKO males lacking. Multiple syngeneic orthotopically implanted tumor models, such as mouse SB28 and GL261 cells, resulted in decreased myeloid recruitment to the TME caused by a reduction of secreted monocytic chemoattractants present in the TME in the NIK^KO mouse brain compared to NIK^WT. Overall, this work strengthens the rationale for developing a therapeutic against NIK for the treatment of GBM due to the combination of tumor intrinsic and extrinsic roles NIK plays in the TME.