Abstract B049: Uncovering sex-biased immunometabolic roles for NIK in the GBM tumor microenvironment

Abstract The interconnected relationship between the central nervous system (CNS) and the immune system is crucial for brain function. Astrocytes, microglia and infiltrating macrophages perform diverse functions for the maintenance of CNS homeostasis, including inflammatory responses to injury or infection, tissue repair and immune surveillance of cancers such as glioblastoma (GBM). Indeed, these cells comprise up to 50% of GBM tumor mass, yet the impact of their interactions in regulating neuroinflammation and immunosuppression in the GBM tumor microenvironment is not well understood. We have recently found that NF-κB-Inducing Kinase (NIK), an essential activator of the noncanonical NF-κB pathway, governs the mitochondrial metabolic reprogramming that is required for the acquisition of pro-repair bone-marrow-derived macrophage (BMDM) immune effector functions. Although NIK is highly expressed in brain immune cells, including resident macrophages/microglia and astrocytes, little is known regarding NIK-dependent regulatory pathways controlling their immune cell effector functions in brain health and systemic responses to disease. Our preliminary data demonstrate that similar to BMDMs, NIK knockout (KO) microglia and astrocytes have impaired mitochondrial oxidative metabolism and skew towards pro-inflammatory phenotypes. Moreover, NIK KO mice harboring orthotopic syngeneic brain tumors exhibit improved survival and reduced microglia and macrophage tumor infiltration, suggesting that NIK functions in the TME to support immune cell interactions that promote GBM growth. Notably these effects were sex-biased, with male NIK KO mice having a more pronounced survival benefit. Additionally, we observe whole-body metabolic dysfunction in myeloid- and astrocyte-specific conditional NIK knockout mice, implying a potential NIK-dependent feedback relationship between CNS immune/glial cell functions and control of systemic metabolism. Overall, these results are consistent with poorer survival of patients with elevated NIK expression and provides a possible rationale for the higher incidence of GBM in males. Coupled with our previous work demonstrating that NIK has several GBM cell-intrinsic roles to promote tumor invasion and adaptive growth through control of mitochondrial fission and cellular metabolism, these new findings highlight the importance of understanding NIK-dependent immunometabolic functions in the brain. Therapeutic strategies targeting NIK may not only attenuate GBM cell invasion and render them vulnerable to metabolic stress, but also modulate metabolic rewiring of immune cells in the tumor microenvironment to improve patient outcomes. Citation Format: Justin N. Keeney, Caren Stuebe, Kathryn M. Pflug, L. Gerard Toussaint, Raquel Sitcheran. Uncovering sex-biased immunometabolic roles for NIK in the GBM tumor microenvironment abstract. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84 (5 Suppl₁): Abstract nr B049.