Overcoming Innate Immune Evasion in Pediatric High Grade Glioma

University of Colorado Denver, AMC and DC, Aurora, CO

Few therapies have been aimed at stimulating the myeloid arm of the immune system to attack tumors. As one of the earliest immunologic defense mechanisms of the developing fetus, the innate immune system, which begins developing during the first trimester of gestation, is a potent cell scavenger within children. We previously showed that anti-CD47 monoclonal antibody activates the innate immune system showing significant activity against high-grade glioma including pediatric glioblastoma and Diffuse intrinsic pontine glioma. However for phagocytosis to occur eat-me signals are required to be exposed on the outer surface of the cells. Depending on the initiating stimulus such as Irradiation, cancer cell death can be immunogenic as they lead to surface expression changes termed, Damage Associated Molecular Patterns which acts as eat me signals marking them for clearance by macrophages. Therefore, there is an overlap in the signals that induce anti-tumor activity in the standard of care therapy and anti-CD47 therapy. Here We hypothesize that irradiating pediatric high-grade glioma tumors, activates DAMP pathways, leading to increased pro-phagocytosis signals on tumor cell surface, making them more susceptible to macrophage-mediated phagocytosis by overcoming the immune evasion mechanisms. Performing these studies we will facilitate a new clinical paradigm.