IMMU-14. WAKING THE SLEEPING GIANT: TLR7/8 AGONIST TREATMENT STIMULATES TUMOR-ASSOCIATED MYELOID CELLS FOR MEDULLOBLASTOMA IMMUNOTHERAPY

Abstract

Abstract Medulloblastomas contain large myeloid populations and we have identified a novel therapy that effectively recruits these non-tumor cells for anti-cancer effect. Medulloblastoma myeloid cells have bivalent functions, supporting tumor growth through IGF1 secretion and immunosuppression, or inhibiting tumor growth through diverse mechanisms including phagocytosis. We investigated a nanoparticle formulation of the TLR7/8 agonist Resiquimod (POx-Resiquimod), administered to Gfap-Cre/SmoM2 (G-Smo) mice that are engineered to develop SHH medulloblastomas, using animal survival time studies, flow cytometry and single-cell trancriptomics (scRNA-seq). POx-Resiquimod treatment increased the survival of G-Smo mice as a single agent and sensitized the typically radiation-resistant G-Smo tumors to radiation therapy. Mechanistically, POx-resiquimod increased the proportions of myeloid cells in medulloblastoma, while blocking IGF1 secretion and re-polarizing the myeloid population from anti-inflammatory to pro-inflammatory. POx-resiquimod induced phagocytosis-related genes, including CD72 and the scavenger receptor MARCO. Functional studies confirmed that POx-resiquidmod increased tumor cell phagocytosis, linking molecular changes to changes in myeloid cell behavior. Our data show that the innate immune function of myeloid cells can be harnessed for medulloblastoma treatment and identify the nanoparticle-delivered TLR7/8 agonist POx-Resiquimod as a specific and effective new agent for medulloblastoma immunotherapy that can be combined with existing modalities.