Medulloblastoma is an aggressive brain tumor that predominantly impacts children. Current treatments can be toxic and neurologically devastating. As such, immunotherapies are promising alternatives. These tumors are notoriously immunosuppressed, with a dearth of anti-tumor processes occurring in the tumor microenvironment. MYCN-amplified Group 3 medulloblastoma is particularly aggressive, with a devastating prognosis. Using a murine model of MYCN-amplified Group 3 medulloblastoma, we seek to uncover and reverse the MYCN-induced chemokine abnormalities in medulloblastoma to drive immune cells towards the tumor site. Of particular interest is restoring tumor expression of CXCL10, though several other cytokines are also under investigation. We are also working on upregulating MHC-I expression on tumor cells to enhance T-cell mediated tumor-killing. EZH2 inhibition is a clinically promising option that we are focusing on and pathways involving MYCN, interferon-gamma, TNF-alpha, and NF-kB.
Ultimately, we hope to enhance T-cell migration, invasion, and tumor-killing, while upregulating MHC-I expression on tumor cells to initiate a robust immune response to these devastating tumors. This project was initiated by Aghi lab postdoc and UCSF neurosurgery resident Taemin Oh and is now being continued by UCSF medical student and yearlong research fellow Ryan Phelps.