Abstract
Immunotherapy has recently emerged as an important strategy for treating cancer, but has not been tested extensively in pediatric brain tumors. To determine whether immunotherapy would be effective in this context, we need robust animal models of brain tumors that have a fully functional immune system. We recently created genetically engineered mouse models of Group 3 (Myc-driven) medulloblastoma, the most aggressive and lethal form of the disease. These models are generated by transducing cerebellar stem cells with viruses encoding Myc and dominant negative p53 (MP model), or Myc and GFI1 (MG model), and transplanting them into the cerebellum of an adult immunodeficient (ID) mouse. To evaluate whether these models can be used to study immunotherapy, we transplanted tumor cells into syngeneic, immunocompetent (IC) hosts. While MP tumors grew robustly in both ID and IC hosts, MG tumors failed to grow when transplanted into IC mice. Depletion of T cells rescued this effect, supporting the notion that MG tumors are being recognized and rejected by the immune system. Notably, knockdown or inactivation of p53 in MG tumors also allowed them to grow in IC hosts, suggesting that p53 mutations may render tumor cells invisible to the immune system. Ongoing studies are focused on understanding the basis of p53-mediated immune regulation, and on developing strategies to overcome it. These studies will provide insight into the interactions between medulloblastoma cells and the immune system, and identify novel approaches to immunotherapy of this tumor. Since p53 is mutated in a large proportion of human cancers, these studies may also have important implications for immunotherapy of other cancers.