THERAPEUTIC MODULATION OF THE PHAGOCYTIC AXIS SPARKS ANTI-TUMOR CD8 T CELL RESPONSES IN GLIOBLASTOMA

As the most common primary brain tumor in adults, Glioblastoma (GBM) remains a major unmet medical need. With current treatment strategies, the median survival remains approximately 15 months, and recurrence occurs in nearly all cases. In this study we examine a novel role for the DNA-methylating agent temozolomide (TMZ) as an activator of innate immunogenicity in GBM. TMZ-mediated DNA damage promotes calreticulin (CRT) translocation to the plasma membrane of cancer cells where it functions as a driver of phagocytosis. Ancillary blockade of anti-phagocytic signaling through Cluster of Differentiation 47 (CD47) further enhances tumor cell uptake by bone-marrow derived macrophages (BMDM). Together these agents promote maturation of BMDM into antigen presenting cells (APCs), capable of initiating effector T cell responses in vitro. We recapitulate these findings in immune-competent preclinical models of GBM, where combination therapy significantly prolongs survival in a cytotoxic CD8+ T cell dependent manner. The results of this study indicate that phagocytic axis modulation is a novel strategy to reprogram the innate immune microenvironment, shifting the dynamic towards an ‘inflamed’ tumor phenotype. This novel approach to immunotherapy in GBM is highly translational and warrants further investigation in the clinical setting.