Pediatric brain tumors have among the highest cancer incidence and are major contributor of mortality and morbidity. Among pediatric brain tumors, medulloblastoma constitutes the most common malignant brain tumors with metastatic potential. Despite aggressive therapy consisting of surgery, radiation, chemotherapy and bone marrow transplantation, survival in high-risk medulloblastoma patients is only about 60%. Recent improved understanding of immune regulation in the central nervous system raises the possibility of cell-based or molecularly targeted immunotherapy to combat this and other deadly CNS-related malignancies. We combine tumor biology and novel insights into CNS immunity by utilizing the unique intravital 2-photon microscopy approach, a technique our lab helped pioneered to visualize dynamic immune cell interaction within live experimental animals, to address fundamental questions critical to the development of effective immune system-based therapies against tumors in the CNS that were previously difficult to ascertain with traditional methods. Specifically, we will study the effects of modulating VCAM-1, a novel surface target of metastatic and aggressive tumors on tumor propagation and outcome of associated immune responses in rodent models. We will test whether targeting VCAM-1 activity in vivo can be efficacious in combating tumors that have found sanctuary in the CNS. Successful implementation of the current proposal will have a high and broad impact across a wide spectrum of scientific arenas, stimulate the development of novel targeted therapy (the 'smart-bomb' approach), and offer real impact on the outcome and quality-of-life measures in patients suffering from the devastating and often deadly CNS malignancies.