IMMU-07. TACEDINALINE (CI994), A CLASS I HDAC INHIBITOR, TARGETS INTRINSIC TUMOR GROWTH AND LEPTOMENINGEAL DISSEMINATION IN MYC-DRIVEN MEDULLOBLASTOMA WHILE MAKING THEM SUSCEPTIBLE TO ANTI-CD47 INDUCED MACROPHAGE PHAGOCYTOSIS VIA NF-KB-TGM2 DRIVEN TUMOR INFLAMMATION

Abstract

Abstract BACKGROUND While major advances have been made in improving the quality of life and survival of children with most forms of medulloblastoma (MB), those with MYC-driven tumors (Grp3-MB) still suffer significant morbidity and mortality. Here, we report a cross-entity, epigenetic drug screen to evaluate therapeutic vulnerabilities in MYC amplified medulloblastoma, which sensitizes them to macrophage-mediated phagocytosis upon targeting the CD47-SIRPa innate checkpoint pathway. METHODS We performed a primary screen including 78 epigenetic inhibitors and a secondary screen including 20 histone deacetylase inhibitors (HDACi) to compare response profiles in atypical teratoid/rhabdoid tumor (AT/RT, n=11), medulloblastoma (n=14), and glioblastoma (n=14). This unbiased approach revealed the preferential activity of HDACi in MYC-driven medulloblastoma. Importantly, the class I selective HDACi, CI-994, showed significant cell viability reduction mediated by induction of apoptosis in MYC-driven medulloblastoma, with little to no activity in non-MYC-driven medulloblastoma, AT/RT, and glioblastoma in vitro. We tested the combinatorial effect of targeting Class I HDACs and the CD47-SIRPa phagocytosis checkpoint pathway using in-vitro phagocytosis assays and in-vivo orthotopic xenograft models. RESULTS CI-994 displayed anti-tumoral effects at the primary site and the metastatic compartment in two orthotopic mouse models of MYC-driven medulloblastoma. Furthermore, RNA sequencing revealed NFκB pathway induction as a response to CI-994 treatment, followed by TGM2 expression, which enhanced inflammatory cytokine secretion. We further show interferon-gamma (IFN-g) release and cell surface expression of engulfment (“eat-me”) signals (such as calreticulin). Finally, combining CI-994 treatment with an anti-CD47 mAb targeting the CD47-SIRPa phagocytosis checkpoint enhanced in vitro phagocytosis and survival in tumor-bearing mice. CONCLUSION Together, these findings suggest a dynamic relationship between MYC amplification and innate immune suppression in MYC-amplified medulloblastoma and support further investigation of phagocytosis modulation as a strategy to enhance cancer immunotherapy responses.