Abstract
BACKGROUND: Medulloblastoma (MB) is the most common pediatric embryonal brain tumor arising in the cerebellum. It has a “cold” tumor microenvironment (TME) characterized by an abundance of immunosuppressive Tumor Associated Macrophages (TAMs) and low T-cell infiltration. TAMs include tissue resident microglia and migrating bone marrow derived macrophages. While microglia play important roles in the central nervous system through their immune surveillance and ability to activate other immune cells, they can be polarized by tumor cells toward an anti-inflammatory state which allows for maintained tumor growth and proliferation. A potential new target to combat the immunosuppressed TME of MB is the class IB isoform PI3Kγ. Inhibiting this isoform has been attributed to controlling a critical switch between immune suppression and immune stimulation in TAMs but has yet to be examined in MB and its TME. We hypothesize that inhibiting PI3Kγ in TAMs and MB tumor cells will induce an anti-tumorigenic immune response within the MB TME and promote tumor clearance. METHODS: Engineered murine MB cells, mCB DNp53 MYC, are treated with a pan-PI3K or specific PI3Kγ inhibitor for 48 hours before being co-cultured with naïve splenic CD4 T-cells from C57BL/6J mice for 5 days. Proliferation of the T cells is measured using Cell Trace Violet through flow cytometry on a Cytek Aurora. RESULTS: Pan-PI3K inhibition revealed that tumor cells treated with the inhibitor prior to co-culturing did not suppress T-cell proliferation as drastically when compared to untreated tumor cells. Treatment with a selective inhibitor is on-going. CONCLUSIONS: These results suggest that inhibition of the PI3K pathway in our MB tumor cells dampens their ability to suppress T cell proliferation. The PI3K pathway may play an active role in tumor cell’s ability to induce immunosuppression. Inhibiting this pathway may be a new avenue for therapeutic intervention for relapsed/refractory MB.