The role of Myeloid cells in pediatric-high grade gliomas

摘要：MPI R01-Hambardzumyan和Becher 儿童高级别胶质瘤(PHGG)占儿童癌症相关死亡人数最多，其中位数为 存活12-15个月。一条很有希望的研究途径是开发针对 肿瘤内非肿瘤细胞类型的特性，例如髓系细胞，包括与肿瘤相关的 巨噬细胞(TAM)和中性粒细胞。人们对成人高级别胶质瘤中的TAMS知之甚多。然而，非常 对PHGG中的TAMs和中性粒细胞知之甚少。PHGG多见于幕下部位 就像脑干一样，超出了成年人的大脑半球。PHGGs还含有明显的组蛋白 在成年人中没有发现突变。这就提出了一个问题，即PHGG是否拥有明显的 TAMs由于其独特的遗传景观和位置。 使用人PHGG组织样本和纳米串RNA测序，我们展示了脑干/中线 PHGGS(DMG)和小鼠弥漫性固有桥脑胶质瘤(DIPG)具有较高的炎症评分和 与半球PHGG相比，中性粒细胞评分增加，这与患者较短的生存期有关。 当只检查人类半球PHGG时，我们的结果显示有两个患者亚组，分别为高和低 炎症评分。与炎症评分高的患者相比，患者的生存时间显著缩短 对于炎症评分较低的患者。我们还发现，人的PHGG对IBA1具有很高的渗透性 TAMs是PHGG肿瘤微环境(TME)中含量最丰富的非肿瘤成分。 我们利用小鼠模型总结新生免疫活性小鼠PHGG的初步数据 与生物学相关部位的各种组蛋白突变表明小鼠肿瘤惊人地相似 在炎症免疫特征和髓系细胞渗透方面与人类同龄人不同。vbl.使用 PDGFB和PDGFA作为小鼠产生半球PHGG的驱动突变，我们能够概括 具有高和低炎症评分的人PHGGs。我们发现，与PDGFA驱动的肿瘤相比， PDGFB肿瘤有更高的炎症评分，从血液中单核细胞的渗透增加，并且较短 荷瘤小鼠的存活时间。我们认为CCL3是CCR1/CCR5阳性的潜在关键趋化因子 单核细胞和CXCL1在PHGG中CXCR2阳性中性粒细胞募集中的作用总而言之，这些结果提供了 有充分的理由扩大我们的研究以了解特定的组蛋白突变和肿瘤位置是如何影响的 髓系细胞的渗透以及这些细胞如何促进PHGG的生长。这些研究的结果如下：(I) PHGG髓系室的分子和功能多样性；(Ii)决定髓系细胞的不同 亚群和髓系特异性基因影响肿瘤生长和TME；(Iii)提供对髓系如何 亚群影响，并受驱动突变、儿科特异性组蛋白突变和肿瘤位置的影响 (大脑半球与脑干)。这项研究还将确定靶向单核细胞和中性粒细胞 渗透将是一种可行的治疗途径来开发PHGG。

Abstract: MPI R01- Hambardzumyan and Becher Pediatric high-grade gliomas (pHGG) account for the most cancer-related deaths in children and have a median survival of 12-15 months. One promising avenue of research is developing novel therapies targeting the properties of non-neoplastic cell types within the tumor, such as myeloid cells, including tumor-associated macrophages (TAMs) and neutrophils. Much is known about TAMs in adult high-grade gliomas. However, very little is known about TAMs and neutrophils in pHGGs. pHGGs more commonly arise in infratentorial locations like the brainstem, beyond the cerebral hemispheres as seen in adults. pHGGs also harbor distinct histone mutations not found in adults. This raises the question of whether pHGGs possess a distinct constituency of TAMs due to their unique genetic landscapes and locations. Using human pHGG tissue samples and NanoString RNA sequencing, we demonstrate brainstem/midline pHGGs (DMG) and murine diffuse intrinsic pontine glioma (DIPG) possess higher inflammatory scores and increased neutrophil scores compared to hemispheric pHGGs, which are associated with shorter patient survival. When examining only human hemispheric pHGGs, our results revealed two patient subsets with high and low inflammatory scores. Patients with a high inflammatory score had significantly shorter survival times compared to those with low inflammatory scores. We also show that human pHGGs possess high infiltration of IBA1+ TAMs, which are the most abundant non-neoplastic component of the pHGG tumor microenvironment (TME). Our preliminary data utilizing mouse models to recapitulate pHGG in newborn immunocompetent mice combined with various histone mutations in biologically relevant locations demonstrate murine tumors are strikingly similar to their human counterparts with regard to their inflammatory immune profile and myeloid cell infiltration. Using PDGFB and PDGFA as driver mutations to generate hemispheric pHGG in mice, we were able to recapitulate human pHGGs with high and low inflammatory scores. We showed that in comparison to PDGFA-driven tumors, PDGFB tumors have a higher inflammatory score, increased infiltration of monocytes from the blood, and shorter survival time of tumor-bearing mice. We identify CCL3 as a potential key chemokine for CCR1/CCR5-positive monocytes and CXCL1 for CXCR2-positive neutrophil recruitment in pHGG. Together, these results provide strong rationale to extend our studies to understand how specific histone mutations and tumor locations influence myeloid cell infiltration and how these cells promote pHGG growth. The outcome of these studies will: (i) reveal the molecular and functional diversity of the myeloid compartment of pHGG; (ii) determine how distinct myeloid subsets and myeloid-specific genes influence tumor growth and the TME; (iii) provide insight into how myeloid subsets influence, and are affected by driver mutations, pediatric-specific histone mutations, and tumor location (hemisphere versus brainstem). This study will also determine whether targeting monocyte and neutrophil infiltration will be a viable therapeutic avenue for exploitation in pHGG.