Contribution of myeloid cells to the anti-tumor adaptive immune response after radiation in a pediatric brain tumor

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Project Summary The goal of the proposed 5-year training program is to facilitate Dr. Mai Dang’s full transition to an independent physician scientist. Her work is focused on identifying novel ways to modulate the brain tumor immune microenvironment to improve treatment strategies for pediatric patients. Dr. Dang’s research background is in neuroscience and her clinical training in pediatric neurology, which was completed at the Children’s Hospital of Philadelphia. After clinical fellowship, she received additional clinical training in neuro- oncology while completing her fellowship research on identifying the heterogeneity of myeloid cells in medulloblastoma. She was recently recruited to Washington University in St. Louis as a tenured-track assistant professor in the Department of Neurology to continue this work with strong institutional support. She will use the next five years of mentored training to acquire additional essential knowledge on immunology and advanced research tools to perform investigations in cancer immunology. While her prior work was specifically on macrophages and microglia, her current proposal will focus on antigen presenting cells and their interaction with the adaptive arm of the immune system. Dr. Dang will be mentored by Dr. Milan Chheda, a physician scientist, whose expertise is on developing new therapies that target glioblastoma brain tumor cancer stem cells and the tumor microenvironment. She will be co-mentored by Dr. David DeNardo, who has expertise in immunology and the tumor microenvironment’s regulation of therapy response in pancreatic and lung cancer. They will be joined by a committee comprised of two highly seasoned mentors, both physician scientists with excellent track record for and commitment to training other physician scientists at WUSTL. Dr. Christine Gurnett is Head of Pediatric neurology, who is highly recognized for her work in the genetics of neurological disorders, and Dr. Joshua Rubin, Professor in Oncology is an expert on pediatric and adult brain tumors. This team is deeply committed to providing Dr. Dang with scientific, technical, and career mentorship to assist her in this launch of her independent research career. The research goal of this proposal is to identify reversible causes of immune suppression in medulloblastomas treated with radiation. The central hypothesis is that effective tumor immunity after radiation in a pediatric brain tumor will require both reducing suppressive myeloid cells and increasing functional antigen presenting cells. She will use advanced tools such as inducible depletion of immune cells and single-cell analysis paired with assays to directly measure the function of antigen presenting cells and cytotoxic T cells to study this hypothesis. Findings from this work will uncover ways to effectively use immunotherapy to augment radiation efficacy to improve overall survival and morbidity for pediatric brain tumor patients.