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.

中文翻译：

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小胶质细胞和单核细胞衍生的巨噬细胞驱动儿科高级别胶质瘤的进展，并受组蛋白突变的转录影响


儿科高级别胶质瘤 （pHGG），包括半球 pHGG 和弥漫性中线胶质瘤 （DMG），具有相互排斥的肿瘤位置特异性组蛋白突变。使用 pHGGs 的免疫活性从头小鼠模型，我们证明髓系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化表明存在由组蛋白突变和肿瘤位置形成的异质性髓系细胞群。在小鼠和人 pHGG 样本中鉴定出表现出免疫允许特性的疾病相关髓系 （DAM） 细胞表型。H3.3K27M DMGs 是最具侵袭性的 DMG，显示出 DAMs 的富集。趋化因子 Ccl8 和 Ccl12 的遗传消融导致 DAM 减少和淋巴细胞浸润增加，导致荷瘤小鼠的存活率增加。趋化因子受体 CCR1 和 CCR5 的药物抑制导致生存期延长并减少髓系细胞浸润。这项工作确定了髓系细胞在 DMG 中的促肿瘤作用以及靶向它们的潜在治疗机会。