肿瘤细胞治疗研究
英文原题：Identification of molecularly targeted therapy-induced immunopeptidome in diffuse midline glioma (DMG).
MTX-241F 改变了胶质瘤免疫肽组，揭示 H2B1K、脑富集免疫肽以及治疗诱导的免疫肽是免疫可见的靶点。
**引言：**携带H3K27M突变的弥漫性中线胶质瘤（DMG）仍是最难治疗的儿童脑肿瘤之一，部分原因在于抗原呈递和免疫识别能力有限。探究胶质瘤生物学及治疗干预如何影响免疫识别，有望发现新的肿瘤特异性免疫靶点。 **材料与方法：**研究对人源细胞系来源的DMG和胶质母细胞瘤（GBM）肿瘤组织进行免疫肽组学分析，并确定选择性EGFR/PI3K抑制剂MTX-241F如何改变肿瘤免疫肽组。研究从异种移植瘤中捕获MHC-I结合肽，再以质谱分离免疫肽；并比较不同肿瘤类型（DMG与GBM）及治疗条件（载体对照与MTX-241F）。 **结果：**免疫肽组分析显示，DMG与GBM的肽库存在肿瘤类型特异差异。GBM肿瘤检出的免疫肽数量约为DMG的两倍，这可能源于两类肿瘤不同的生物学特征，也可能反映HLA等位基因组成不同。研究在DMG中发现大量H2B1K来源免疫肽，提示H3K27M驱动的表观转录组变化可能促进其他组蛋白周转。MTX-241F使DMG中的免疫肽数量增加，却使GBM中的数量减少，表明EGFR/PI3K抑制后免疫肽组的变化具有肿瘤类型特异性。此外，研究发现富集于脑组织、可结合HLA-A*02:01且仅在MTX-241F治疗后出现的免疫肽；这些肽反映治疗诱导的变化，可能用作疗效生物标志物或CAR-T细胞疗法的潜在靶点。 **讨论：**MTX-241F可改变胶质瘤免疫肽组，揭示H2B1K、脑组织富集及治疗诱导的免疫肽可作为免疫系统识别的靶点。这些发现为将分子靶向治疗与免疫疗法结合、增强DMG和GBM的肿瘤识别及治疗效果提供了依据。
INTRODUCTION: Diffuse midline glioma (DMG) with the H3K27M mutation remains one of the most treatment-resistant pediatric brain tumors, in part due to limited antigen presentation and immune visibility. Exploring how glioma biology and therapeutic interventions influence immune recognition offers new opportunities to identify tumor-specific immune targets. MATERIALS AND METHODS: We performed immunopeptidomics on human cell line derived tumor tissue for DMG and glioblastoma (GBM) and defined how MTX-241F, a selective EGFR/PI3K inhibitor, changes the tumor immunopeptidome. Immunopeptides were isolated from xenografted tumors by capturing MHC-I bound peptides followed by mass spectrometry. Comparative analyses were performed across tumor type (DMG vs. GBM) and treatment condition (vehicle vs. MTX-241F). RESULTS: Immunopeptidomic profiling revealed tumor-specific differences in peptide repertoires between DMG and GBM. GBM tumors exhibited twice as many immunopeptides as DMG, which may be due to the distinct biology of each tumor type or may be indicative of potential HLA allotype composition. We identified highly abundant H2B1K-derived immunopeptides in DMG, suggesting that the H3K27M-driven epitranscriptome may promote turnover of other histones. MTX-241F increased the number of immunopeptides in DMG but reduced them in GBM, indicating a tumor-specific change in the immunopeptidome following EGFR/PI3K inhibition. In addition, we identified brain-enriched, HLA-A*02:01-binding and MTX-241F-exclusive immunopeptides that represent treatment-induced changes and may serve as biomarkers of therapeutic response or potential targets for CAR-T cell-based approaches. DISCUSSION: MTX-241F changes the glioma immunopeptidome, unveiling H2B1K, brain-enriched, and treatment-induced immunopeptides as immunologically visible targets. These findings provide a rationale for integrating molecularly targeted therapy with immunotherapeutic approaches to enhance tumor recognition and treatment efficacy in DMG and GBM.
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