A NOVEL TGF-BETA/MYC-DRIVI-tN MEDULLOBLASTOMA MODEL TO STUDY IMMUNE-TUMOR INTERACTIONS

Developing authentic mouse models of medulloblastoma (MB) is vitally important for understanding MB biology and developing novel treatments for patients with this disease. In particular, models with a native immune system are critical for deciphering the complex roles that immune escape and surveillance play in MB formation and eradication, respectively. We previously reported that components of the TGFb signaling pathway are necessary for Group 3 MYC-amplified MB proliferation and survival. We have also observed that small molecule inhibition of the TGFb pathway primes MB for immune checkpoint allowing for increased T cell infiltration in an otherwise “immunodepleted” tumor. Here, we sought to determine whether TGFb signaling in cooperation with MYC was sufficient to transform cells into MB. Toward this end, we isolated cerebellar stem cells from 4–6 week old mice and transduced them with lentiviral vectors expressing either a constitutively active TGFbR1 (ALK5) or MYC, or both. Cells transduced with both ALK5 and MYC, but not each individually, quickly formed dense neurospheres in vitro that propagated ad infinitum. When allografted into either immunodeficient or syngeneic immune competent mice, these transformed cells formed large, infiltrating tumors, that displayed nuclear atypia and other features reminiscent of anaplastic MB. Gene expression microarray analysis further confirmed an expression signature consistent with previously published Group 3 MYC-amplified MB mouse models (GTML; MYC-DNp53) as well as human primary Group 3 MB. Interestingly, tumors generated from TGFb/MYC-transformed cells allografted into syngeneic immune competent mice lacked T cell infiltration and had dysfunctional neoantigen presenting machinery consistent with the human condition. Thus, we provide a novel Group 3 TGFb/MYC-driven MB model that closely recapitulates the human condition and will serve as a useful resource to better understand mechanisms of tumor-immune interactions in MB. SIGNALING