Predicting and Overcoming Resistance to Immunotherapy in Pediatric High-Grade Glioma
Immunotherapy has emerged as a powerful approach to treating cancer, but only a subset of patients respond, and the remainder suffer severe side effects without benefiting from the therapy. There is a critical need to understand the factors that limit success of this approach, and to develop strategies to enhance responsiveness. Most immunotherapies involve killing of tumor cells by cells of the immune system called "T cells". For T cells to attack tumors, the tumors must have a protein called MHC on their surface; if tumor cells have no MHC, they cannot be targeted by T cells. Our work focuses on immunotherapy for pediatric high-grade gliomas (pHGG), the leading cause of death in children with brain tumors. We recently identified a mutation that leads to loss of MHC on pHGG cells. Tumors that carry this mutation are invisible to immune cells and insensitive to many immunotherapy approaches.
Our studies to date have focused on animal models, and it is not known whether this mutation causes loss of MHC in human pHGG. If so, patients with this mutation might be unresponsive to immunotherapy. Importantly, we have also identified proteins that can restore MHC expression in tumor cells carrying the mutation. We hypothesize that these proteins could be used in conjunction with immunotherapy to turn on expression of MHC and render tumors more sensitive to T cell attack. If successful, the work proposed here will pave the way toward more effective use of immunotherapy for patients with pHGG and other pediatric cancers.