EphA2 and phosphoantigen-mediated selective killing of medulloblastoma by γδT cells preserves neuronal and stem cell integrity.

in Oncoimmunology by Lola Boutin, Mingzhi Liu, Julie Déchanet Merville, Oscar Bedoya-Reina, Margareta T Wilhelm

TLDR

  • The study explores the therapeutic potential of Gamma Delta T cells against Medulloblastoma, a common pediatric brain cancer, and found that these cells can target and kill cancer cells while sparing healthy brain cells.
  • The results suggest that Gamma Delta T cells could provide a promising novel therapeutic strategy for Medulloblastoma treatment, offering less toxic and more effective alternatives to current standard treatments.

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 treatments include surgery, chemotherapy, and radiation, but despite a 5-y 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 (γδ)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 γδT cells against MB, we analyzed the proportion and status of MB-infiltrated γδT cells within patient datasets. We next investigated the expression of γδT cell ligands on MB cells and identified the EphA2 receptor and the phosphoantigen/Butyrophilin complex as key ligands, activating Vγ9 Vδ1 and Vγ9 Vδ2 T cells, respectively, leading to significant MB cell lysis in both monolayer and spheroid models. Importantly, preliminary safety data showed that γδT 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, γδT cells trigger an efficient and specific killing of MB and would offer a promising novel therapeutic strategy.

Overview

  • The study investigates the therapeutic potential of Gamma Delta (γδ)T cells against Medulloblastoma (MB), a common pediatric brain cancer.
  • The researchers analyzed patient datasets to identify the proportion and status of MB-infiltrated γδT cells and investigated the expression of γδT cell ligands on MB cells.
  • The primary objective is to explore the potential of γδT cells as a less toxic, more effective therapeutic alternative for MB treatment, considering the limitations of current standard treatments.

Comparative Analysis & Findings

  • The study identified EphA2 receptor and the phosphoantigen/Butyrophilin complex as key ligands on MB cells that activate Vγ9 Vδ1 and Vγ9 Vδ2 T cells, respectively, leading to significant MB cell lysis.
  • γδT cells were found to target MB cells while sparing differentiated neurons and neuroepithelial stem cells, demonstrating the selectivity and safety of this approach.
  • The results show that γδT cells trigger an efficient and specific killing of MB cells in both monolayer and spheroid models, highlighting their potential as a novel therapeutic strategy for MB treatment.

Implications and Future Directions

  • The findings of this study suggest that γδT cells could provide a promising novel therapeutic strategy for MB treatment, offering less toxic and more effective alternatives to current standard treatments.
  • Future studies should investigate the optimal use of γδT cells in combination with other cancer immunotherapies to enhance their therapeutic potential.
  • The selective targeting of MB cells and sparing of non-tumor cells highlights the potential of γδT cells for pediatric brain cancer treatment, warranting further development and clinical evaluation.
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