Piyadasa Hadeesha, Oberlton Benjamin, Ribi Mikaela, Ranek Jolene S, Averbukh Inna, Leow Ke, Amouzgar Meelad, Liu Candace C, Greenwald Noah F, McCaffrey Erin F, Kumar Rashmi, Ferrian Selena, Tsai Albert G, Filiz Ferda, Fullaway Christine Camacho, Bosse Marc, Varra Sricharan Reddy, Kong Alex, Sowers Cameron, Gephart Melanie Hayden, Nuñez-Perez Pablo, Yang EnJun, Travers Mike, Schachter Michael J, Liang Samantha, Santi Maria R, Bucktrout Samantha, Gherardini Pier Federico, Connolly John, Cole Kristina, Barish Michael E, Brown Christine E, Oldridge Derek A, Drake Richard R, Phillips Joanna J, Okada Hideho, Prins Robert, Bendall Sean C, Angelo Michael
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
Immunology Program, Stanford University School of Medicine, Stanford, CA, USA.
bioRxiv. 2025 Apr 9:2025.03.12.642624. doi: 10.1101/2025.03.12.642624.
Gliomas are among the most lethal cancers, with limited treatment options. To uncover hallmarks of therapeutic escape and tumor microenvironment (TME) evolution, we applied spatial proteomics, transcriptomics, and glycomics to 670 lesions from 310 adult and pediatric patients. Single-cell analysis shows high B7H3+ tumor cell prevalence in glioblastoma (GBM) and pleomorphic xanthoastrocytoma (PXA), while most gliomas, including pediatric cases, express targetable tumor antigens in less than 50% of tumor cells, potentially explaining trial failures. Longitudinal samples of isocitrate dehydrogenase (IDH)-mutant gliomas reveal recurrence driven by tumor-immune spatial reorganization, shifting from T-cell and vasculature-associated myeloid cell-enriched niches to microglia and CD206+ macrophage-dominated tumors. Multi-omic integration identified N-glycosylation as the best classifier of grade, while the immune transcriptome best predicted GBM survival. Provided as a community resource, this study opens new avenues for glioma targeting, classification, outcome prediction, and a baseline of TME composition across all stages.
神经胶质瘤是最致命的癌症之一，治疗选择有限。为了揭示治疗逃逸和肿瘤微环境（TME）演变的特征，我们对310名成人和儿童患者的670个病灶进行了空间蛋白质组学、转录组学和糖组学分析。单细胞分析显示，在胶质母细胞瘤（GBM）和多形性黄色星形细胞瘤（PXA）中，B7H3+肿瘤细胞的患病率很高，而大多数神经胶质瘤，包括儿科病例，在不到50%的肿瘤细胞中表达可靶向的肿瘤抗原，这可能解释了试验失败的原因。异柠檬酸脱氢酶（IDH）突变型神经胶质瘤的纵向样本显示，复发是由肿瘤免疫空间重组驱动的，从富含T细胞和血管相关髓样细胞的微环境转变为以小胶质细胞和CD206+巨噬细胞为主的肿瘤。多组学整合确定N-糖基化是分级的最佳分类器，而免疫转录组最能预测GBM的生存期。作为一项社区资源，本研究为神经胶质瘤的靶向治疗、分类、预后预测以及所有阶段TME组成的基线提供了新途径。
