儿童高级神经胶质瘤 (pHGG)，包括半球 pHGG 和弥漫性中线神经胶质瘤 (DMG)，具有相互排斥的肿瘤位置特异性组蛋白突变。使用具有免疫功能的 pHGG 新生小鼠模型，我们证明骨髓细胞是主要的浸润性非肿瘤细胞群。单细胞 RNA 测序 (scRNA-seq)、流式细胞术和免疫组织化学表明存在由组蛋白突变和肿瘤位置形成的异质性骨髓细胞群。在小鼠和人类 pHGG 样本中鉴定出表现出免疫许可特征的疾病相关骨髓 (DAM) 细胞表型。 H3.3K27M DMG 是最具攻击性的 DMG，显示出 DAM 的富集。趋化因子 Ccl8 和 Ccl12 的基因消除导致 DAM 减少和淋巴细胞浸润增加，从而提高荷瘤小鼠的存活率。趋化因子受体 CCR1 和 CCR5 的药物抑制可延长生存期并减少骨髓细胞浸润。这项工作确立了骨髓细胞在 DMG 中的促肿瘤作用以及针对它们的潜在治疗机会。版权所有 © 2024 Elsevier Inc. 保留所有权利。

Pediatric high-grade gliomas (pHGGs), including hemispheric pHGGs and diffuse midline gliomas (DMGs), harbor mutually exclusive tumor location-specific histone mutations. Using immunocompetent de novo mouse models of pHGGs, we demonstrated that myeloid cells were the predominant infiltrating non-neoplastic cell population. Single-cell RNA sequencing (scRNA-seq), flow cytometry, and immunohistochemistry illustrated the presence of heterogeneous myeloid cell populations shaped by histone mutations and tumor location. Disease-associated myeloid (DAM) cell phenotypes demonstrating immune permissive characteristics were identified in murine and human pHGG samples. H3.3K27M DMGs, the most aggressive DMG, demonstrated enrichment of DAMs. Genetic ablation of chemokines Ccl8 and Ccl12 resulted in a reduction of DAMs and an increase in lymphocyte infiltration, leading to increased survival of tumor-bearing mice. Pharmacologic inhibition of chemokine receptors CCR1 and CCR5 resulted in extended survival and decreased myeloid cell infiltration. This work establishes the tumor-promoting role of myeloid cells in DMG and the potential therapeutic opportunities for targeting them.Copyright © 2024 Elsevier Inc. All rights reserved.