Epigenetic modulation of NKG2D ligands enhances NKG2D-CAR T cell efficacy in neuroblastoma.
9 affiliations
- 1Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy, IdiPAZ, La Paz University Hospital, CIBERER-ISCIII, Madrid, Spain.
- 2Pediatric Onco-Hematology Clinical Research Unit, IdiPAZ-CNIO (Spanish National Cancer Research Center), Madrid, Spain.
- 3Pathology Department, La Paz University Hospital, Madrid, Spain.
- 4Advanced Therapies Mixed Unit, CIEMAT/IIS-FJD, Madrid, Spain.
- 5Translational Research in Pediatric Oncology, Hematopoietic Transplantation and Cell Therapy, IdiPAZ, La Paz University Hospital, CIBERER-ISCIII, Madrid, Spain. [email protected].
- 6Pediatric Onco-Hematology Clinical Research Unit, IdiPAZ-CNIO (Spanish National Cancer Research Center), Madrid, Spain. [email protected].
- 7Pediatric Hemato-Oncology Department, La Paz University Hospital, Madrid, Spain. [email protected].
- 8Pediatric Department, Autonomous University of Madrid, Madrid, Spain. [email protected].
- 9Pediatric Onco-Hematology Clinical Research Unit, IdiPAZ-CNIO (Spanish National Cancer Research Center), Madrid, Spain. [email protected].
Abstract
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.
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BibTeX
@article{navarrozapata2026epigenetic,
title = {{Epigenetic modulation of NKG2D ligands enhances NKG2D-CAR T cell efficacy in neuroblastoma.}},
author = {Alfonso Navarro-Zapata and María Octavia De Santisteban and Rita María Regojo-Zapata and Marta Ibáñez-Navarro and Laura Clares-Villa and Marta de la Hoz and Andrea Romero and Carmen Mestre-Durán and Karima Al-Akioui Sanz and Halin Bareke and Sara Naharro and Jordi Minguillón and Lidia Pertíñez and Natalia Riestra and Mireia Masot and Carla Martín-Cortázar and Cristina Aguirre-Portolés and Cristina Ferreras and Adriana Mañas and Antonio Pérez-Martínez and Lucía Fernández Casanova},
journal = {Journal of translational medicine},
year = {2026},
month = jul,
doi = {10.1186/s12967-026-08685-y},
url = {https://europepmc.org/article/MED/42902385},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Epigenetic modulation of NKG2D ligands enhances NKG2D-CAR T cell efficacy in neuroblastoma.
AU - Alfonso Navarro-Zapata
AU - María Octavia De Santisteban
AU - Rita María Regojo-Zapata
AU - Marta Ibáñez-Navarro
AU - Laura Clares-Villa
AU - Marta de la Hoz
AU - Andrea Romero
AU - Carmen Mestre-Durán
AU - Karima Al-Akioui Sanz
AU - Halin Bareke
AU - Sara Naharro
AU - Jordi Minguillón
AU - Lidia Pertíñez
AU - Natalia Riestra
AU - Mireia Masot
AU - Carla Martín-Cortázar
AU - Cristina Aguirre-Portolés
AU - Cristina Ferreras
AU - Adriana Mañas
AU - Antonio Pérez-Martínez
AU - Lucía Fernández Casanova
PY - 2026
DA - 2026/07/01
JO - Journal of translational medicine
DO - 10.1186/s12967-026-08685-y
UR - https://europepmc.org/article/MED/42902385
AB - 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.
SN - 1479-5876
ER -