Journal Article

Targeting the HLA-E–NKG2A axis in combination with MS-275 enhances NK cell-based immunotherapy against DMG

Zhang, Liwei, Xie, Luyang, Feng, Jie, Pu, Zhuonan, Zhang, Xiaoli, Wang, Yi, Deng, Yuxuan, Liu, Jinqiu, Li, Tian, Jiang, Zhuang, Du, Chao, Zhuang, Zhengping, Hao, Shuyu, Chen, YingDan, Yang, Mingxu, Ji, Nan

2025

Overview

Background Diffuse midline glioma (DMG) is an aggressive pediatric brain tumor with limited treatment options. Although natural killer (NK) cell-based immunotherapy is promising, its efficacy remains limited, necessitating strategies to enhance NK cell cytotoxicity. Histone deacetylase (HDAC) inhibition demonstrate potential to enhance NK-mediated killing. However, the combination of HDAC inhibitors and NK cell therapy for DMG remains unexplored. Methods Patient-derived DMG cell lines and orthotopic mouse models were used to evaluate the effects of the class I HDAC inhibitor MS-275 on cytotoxicity. NK cell-mediated lysis was measured using both luciferase and calcein AM-based assays. The downstream signaling pathways affected by MS-275 were investigated via RNA-seq, CUT&Tag assay, RT‒qPCR, and chromatin immunoprecipitation with qPCR. Results Based on bioinformatic analysis, class I HDACs are identified as therapeutic targets in DMG. The corresponding HDAC inhibitor, MS-275 upregulated NK cell-mediated cytotoxicity pathway through GSEA analysis. Pretreating DMG cells with MS-275 elevated NK cell ligand gene expression and enhanced NK cell-induced lysis. In addition to NK-activating ligands, MS-275 elevated the NK-inhibitory ligand HLA-E, thereby enhancing the efficacy of immunotherapies targeting the NKG2A–HLA-E axis. Mechanistically, MS-275 increased HLA-E expression by promoting STAT3 acetylation at lysine 685. Combining MS-275 with NK cell therapy and blockade of the NKG2A–HLA-E axis extended overall survival in orthotopic mouse models. Conclusions This study is the first to demonstrate that HDAC inhibition enhances NK cell-mediated cytotoxicity in DMG. Combining HDAC inhibition with NK cell therapy represents a promising therapeutic strategy for treating DMG by targeting NKG2A–HLA-E axis.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Animals / Antigens / Apoptosis / Benzamides - pharmacology / Benzamides - therapeutic use / Biomedical and Life Sciences / Biomedicine / Brain cancer / Brain tumors / Cancer Research / Cell cycle / Cell growth / Cell Line, Tumor / Chromatin / Clinical trials / Diffuse midline glioma (DMG) / Disease Models, Animal / Ethylenediaminetetraacetic acid / Gene expression / Genes / Glioma / Glioma - drug therapy / Glioma - immunology / Glioma - pathology / Glioma - therapy / Gliomas / Histocompatibility antigens / Histocompatibility Antigens Class I - metabolism / Histone deacetylase (HDAC) / Histone Deacetylase Inhibitors - pharmacology / HLA histocompatibility antigens / HLA-E / HLA-E Antigens / Humans / Immunology / Immunotherapy / Immunotherapy - methods / Killer cells / Killer Cells, Natural - immunology / Killer Cells, Natural - metabolism / Ligands / Luciferase / Mice / Natural killer (NK) cell / NK Cell Lectin-Like Receptor Subfamily C - metabolism / Oncology / Pyridines - pharmacology / Pyridines - therapeutic use / Reagents / RNA / Software / Tumors / Xenograft Model Antitumor Assays