The role of Myeloid cells in pediatric-high grade gliomas

骨髓细胞在儿童高级别胶质瘤中的作用

基本信息

批准号：
10626717
负责人：
Oren Josh Becher
金额：
$ 67.54万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10626717
关键词：
Address Adult Affect Anatomy Antineoplastic Agents Automobile Driving Biological Assay Blood Blood Circulation Bone Marrow Brain Brain Stem CCL3 gene CCR1 gene CCR5 gene CXCL1 gene Cell Communication Cells Central Nervous System Cerebral hemisphere Cessation of life Child Childhood Childhood Brain Neoplasm Childhood Glioma Clinical Combined Modality Therapy Complement DNA copy number Data Diffuse intrinsic pontine glioma Disease Flow Cytometry Foundations Gene Expression Gene Expression Profile Genes Genetic Genetic Engineering Genetically Engineered Mouse Genomics Genotype Glioma Goals Growth Heterogeneity Histones Human IL8RB gene Immune Immunocompetent Immunofluorescence Immunologic In Vitro Infiltration Inflammatory Invaded Knowledge Location Macrophage Malignant Childhood Neoplasm Microglia Modality Modeling Molecular Molecular Profiling Mus Mutation Myelogenous Myeloid Cells Nature Neutrophil Infiltration Newborn Infant Oncogenic Outcome Study PDGFA gene PDGFB gene Patients Population Prognosis Property Radiation Research Role Sampling Slice T-Lymphocyte Testing Therapeutic Time Tissue Sample Tumor Promotion Tumor-associated macrophages cell type chemokine childhood cancer mortality clinically relevant design driver mutation insight monocyte mouse model nano-string neutrophil new therapeutic target novel patient subsets pharmacologic public health relevance recruit response single-cell RNA sequencing standard of care targeted treatment tool transcriptome sequencing tumor tumor growth tumor microenvironment tumor progression tumor-immune system interactions

项目摘要

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.

摘要：MPI R01-Hambardzumyan 和 Becher 儿童高级别胶质瘤 (pHGG) 是导致儿童癌症相关死亡人数最多的原因，并且中位数为生存期12-15个月。一种有前途的研究途径是开发针对肿瘤内非肿瘤细胞类型的特性，例如骨髓细胞，包括肿瘤相关细胞巨噬细胞 (TAM) 和中性粒细胞。关于成人高级别神经胶质瘤中的 TAM 已有很多了解。然而，非常关于 pHGG 中的 TAM 和中性粒细胞知之甚少。 pHGG 更常见于幕下位置就像成人中看到的脑干一样，超出了大脑半球。 pHGG 还具有独特的组蛋白成人中未发现的突变。这就提出了一个问题：pHGG 是否拥有独特的选区 TAM 由于其独特的遗传景观和位置。使用人类 pHGG 组织样本和 NanoString RNA 测序，我们展示了脑干/中线 pHGGs (DMG) 和小鼠弥漫性内源性脑桥胶质瘤 (DIPG) 具有较高的炎症评分，并且与半球 pHGG 相比，中性粒细胞评分增加，这与患者生存期较短有关。当仅检查人类半球 pHGG 时，我们的结果显示了两个具有高和低 pHGG 的患者子集炎症评分。与炎症评分高的患者相比，其生存时间显着缩短对于那些炎症评分较低的人。我们还表明，人类 pHGG 具有 IBA1+ 的高渗透性 TAM，是 pHGG 肿瘤微环境 (TME) 中最丰富的非肿瘤成分。我们利用小鼠模型重现新生免疫活性小鼠的 pHGG 的初步数据在生物学相关位置存在各种组蛋白突变，表明小鼠肿瘤具有惊人的相似性在炎症免疫特征和骨髓细胞浸润方面与人类同行相似。使用 PDGFB 和 PDGFA 作为驱动突变在小鼠中产生半球 pHGG，我们能够概括具有高和低炎症评分的人类 pHGG。我们发现，与 PDGFA 驱动的肿瘤相比， PDGFB肿瘤具有较高的炎症评分、血液中单核细胞的浸润增加以及较短的荷瘤小鼠的存活时间。我们确定 CCL3 是 CCR1/CCR5 阳性的潜在关键趋化因子单核细胞和 CXCL1 用于 pHGG 中 CXCR2 阳性中性粒细胞的募集。这些结果共同提供了扩展我们的研究以了解特定组蛋白突变和肿瘤位置如何影响的强有力的理由骨髓细胞浸润以及这些细胞如何促进 pHGG 生长。这些研究的结果将：（i）揭示 pHGG 骨髓区室的分子和功能多样性； (ii) 确定骨髓细胞的不同程度子集和骨髓特异性基因影响肿瘤生长和 TME； (iii) 深入了解骨髓细胞如何子集影响驱动突变、儿科特异性组蛋白突变和肿瘤位置，并受驱动突变、儿科特异性组蛋白突变和肿瘤位置的影响（半球与脑干）。这项研究还将确定是否针对单核细胞和中性粒细胞渗透将是 pHGG 中可行的治疗途径。