Epigenetic modulation of NKG2D ligands enhances NKG2D-CAR T cell efficacy in neuroblastoma.
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BACKGROUND: Neuroblastoma (NB) is the most common extracranial solid tumor in children and is associated with high mortality despite aggressive multimodal therapies for high-risk patients. Novel treatments such as CAR T cell therapy offer promise, yet challenges persist due to immune evasion mechanisms by tumor cells. Specifically, the interaction between the natural killer group 2D (NKG2D) receptor on cytotoxic immune cells and its ligands (NKG2DL) is critical for antitumor immunity. However, the expression of NKG2DL is tightly regulated by different means, including epigenetic mechanisms. NB cells often downregulate NKG2DL expression to evade immune control, and this reduction is associated with poorer survival and worse prognosis. METHODS: The NKG2DL expression was assessed in a set of NB cell lines and patient-derived xenograft organoids (PDXOs) under basal conditions and following treatment with epigenetic drugs, valproic acid (VPA) and tazemetostat (TZM). NKG2D-CAR T cells were generated, and their proliferation, phenotype, cell-killing assays and cytokine production were performed in vitro. Cell-based assays were performed combining epigenetic drugs and NKG2D-CAR T cells in the different NB models. RESULTS: Our study revealed that NKG2DL expression in NB models and patient samples exhibited considerable heterogeneity, but it was low overall. Although NKG2DL expression does not necessarily preclude susceptibility, its downregulation may compromise the cytotoxicity of NKG2D-CAR T cells. Treatment with epigenetic drugs, VPA and TZM, significantly increased NKG2DL expression and improved NKG2D-CAR T cell-mediated killing in vitro and in vivo. CONCLUSION: This work suggests that targeting epigenetic pathways can enhance the susceptibility of NB cells to NKG2D-CAR T cell therapy, thereby providing a potential new approach to treat high-risk NB.