Targeting EPHB2/ABL1 restores anti-tumor immunity in a preclinical model of ependymoma 2418

Description Ependymoma (EPN) is a childhood brain tumor that is resistant to current therapy. Recent molecular profiling identified unique EPN subtypes. Therefore, desperately needed new treatments for EPN should be developed in a molecular subtype-specific manner. We developed a mouse model using ephrin receptor B2 (EPHB2) subtype-driven genetically engineered EPN tumor cells. Druggable targets were identified by matching transcriptomic signatures with the target spectrum of FDA-approved drugs and revealed multiple protein kinases as possible targets. We identified that the multikinase inhibitor dasatinib inhibited EPN growth through blocking EPHB2 and ABL1 signaling. We measured changes in the immune microenvironment during EPN growth and after dasatinib treatment and found an increased frequency of immunosuppressive tumor-associated macrophages (TAMs), which proportionally increased with tumor size during tumor progression. However, dasatinib reprogrammed the EPN immune microenvironment by polarizing TAMs toward an anti-tumor phenotype and increasing dendritic cell maturation and CD8 T cell activation. Furthermore, dasatinib induced complete regression of established EPN tumors in 78% of animals and generated immunological memory to protect survivors against recurrence. These data indicate that dasatinib may be an effective therapy for EPHB2-driven molecular subgroup of EPNs by activating the anti-tumor immune response and support further investigations of dasatinib in clinical trials. Funding Sources R35-CA197743; R01- R01CA259253; R01-CA269672; R01-NS118929; U01-CA224348; U01-CA261842; NIH 5T32CA272386. National Foundation for Cancer Research, Harvard Ludwig Cancer Center, Nile Albright Research Foundation, Jane’s Trust Foundation, Fund for Medical Discovery Fellowship from Massachusetts General Hospital. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)