Preclinical assessment of checkpoint blockade combined with DNA methyltransferase inhibition in high-risk pediatric brain tumors reveals limited therapeutic synergy

作者：Deepak Mishra, Shelli M. Morris, Dean Popovski, Emily J Girard, Andrew Bondoc, Shiva Senthil Kumar, Augusto Faria Andrade, Xiaoting Zhu, Fupan Yao, Mi‐Youn Brusniak, Banlanjo Abdulaziz Umaru, Erin Crotty, Ken Brasel, Fiona Pakiam, Caterina Russo, Michele Zeinieh, Matthew C. Biery, Margo Coxon, Heather R. Conti, Midori Clarke, Mei Lu, James T. Rutka, Dhana Llivichuzhca-Loja, Liza Konnikova, Maryam Fouladi, Nada Jabado, Annie Huang, James M. Olson, Rachid Drissi · 发表于：Neuro-Oncology Advances · 年份：2025 · DOI：10.1093/noajnl/vdaf241 · 被引用次数：5 · 研究领域：Glioma Diagnosis and Treatment、Cancer Immunotherapy and Biomarkers、Epigenetics and DNA Methylation

Abstract: BackgroundDespite intensive therapies, outcomes for high-risk pediatric brain tumors (PBTs) remain dismal, prompting the search for novel treatments. DNA methyltransferase inhibitors (DNMTi) have been shown to prime tumors to improve response to checkpoint inhibition. The aim of this study was to investigate the potential of decitabine (DAC), in combination with a PD-1 inhibitor, to improve survival in pediatric high-risk brain tumor models. Methods: Analysis of human PBT datasets was performed to determine gene expression levels of immune cell markers. Tumor response to DAC, with or without a PD-1 inhibitor, was tested in murine models representing H3-wildtype diffuse intrinsic pontine glioma (DIPG), H3K27-mutant diffuse midline glioma (DMG), atypical teratoid rhabdoid tumor (ATRT), and medulloblastoma (MB). CyTOF analysis of allograft tumors was performed to characterize changes within the tumor microenvironment. Results: Analysis of PBT subtypes revealed heterogeneous expression of immune cell markers, checkpoint receptors, and MHC molecules. DAC treatment decreased DNA methylation and increased neoantigen expression in human and mouse tumor cells. DAC treatment resulted in prolonged survival in syngeneic mouse models of DIPG and ATRT but not DMG and MB models. However, no added survival benefit was observed when combined with a PD-1 inhibitor. CyTOF analysis of mouse tumors revealed changes in local immune cell infiltration. Conclusions: DAC alone or in combinat...