Ephrin-A2 and Phosphoantigen-Mediated Selective Killing of Medulloblastoma by γδT Cells Preserves Neuronal and Stem Cell Integrity

Abstract

Medulloblastoma (MB) is a pediatric brain tumor that develops in the cerebellum, representing one of the most common malignant brain cancers in children. Standard treatment includes surgery, chemotherapy, and radiation, but despite a 5-year survival rate of approximately 70%, these therapies often lead to significant neurological damage in the developing brain. This underscores the urgent need for less toxic, more effective therapeutic alternatives. Recent advancements in cancer immunotherapy, including immune checkpoint inhibitors and CAR-T cell therapy, have revolutionized cancer treatment. One promising avenue is the use of Gamma Delta ({gamma}{delta})T cells, a unique T cell population with potential advantages such as non-alloreactivity, potent tumor cell lysis, and broad antigen recognition. However, their capacity to recognize and target MB cells remains underexplored. To investigate the therapeutic potential of {gamma}{delta}T cells against MB, we analyzed the proportion and status of MB-infiltrated {gamma}{delta}T cells within patient datasets. We next investigated the expression of {gamma}{delta}T cell ligands on MB cells and identified EphA2 receptor and the phosphoantigen/Butyrophilin complex as key ligands, activating V{gamma}9V{delta}1 and V{gamma}9V{delta}2 T cells, respectively, leading to significant MB cell lysis in both monolayer and spheroid models. Importantly, preliminary safety data showed that {gamma}{delta}T cells did not target differentiated neurons or neuroepithelial stem cells derived from induced pluripotent stem cells, underscoring the selectivity and safety of this approach. In conclusion, {gamma}{delta}T cells trigger an efficient and specific killing of MB, and would offer a promising novel therapeutic strategy. Key messagesMedulloblastoma patients often experience significant long-term side effects from current standard treatments. Immunotherapy has emerged as a promising alternative to conventional therapeutic approaches. In our study, we demonstrated that {gamma}{delta}T cells can efficiently and specifically target medulloblastoma cells without causing harm to healthy neuronal tissue. These findings suggest that {gamma}{delta} T cell therapy may provide therapeutic benefits while potentially reducing treatment-related toxicity in medulloblastoma patients.