权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10391024
负责人：
Oren Josh Becher
金额：
$ 68.61万
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/10391024
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 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 Gold Growth Heterogeneity Histones Human IL8RB gene Immune Immunocompetent Immunofluorescence Immunologic In Vitro Infiltration Inflammatory Invaded Knowledge Location Malignant Childhood Neoplasm Microglia Modality Modeling Molecular Molecular Profiling Mus Mutation Myelogenous Myeloid Cells Nature Neuraxis Neutrophil Infiltration Newborn Infant Oncogenic Outcome Study PDGFA gene PDGFB gene Patients Pharmacology Population Prognosis Property Radiation Research Role Sampling Slice T-Lymphocyte Testing Therapeutic Time Tissue Sample Tumor-associated macrophages cell type chemokine childhood cancer mortality clinically relevant design driver mutation insight macrophage monocyte mouse model nano-string neutrophil new therapeutic target novel patient subsets 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 R 01- Hambardzumyan和Becher 儿童高级别胶质瘤（pHGG）占儿童癌症相关死亡的比例最高，存活12-15个月。一个有希望的研究途径是开发针对肿瘤内的非肿瘤细胞类型的性质，例如骨髓细胞，包括肿瘤相关的巨噬细胞（TAM）和嗜中性粒细胞。我们对成人高级别胶质瘤中的TAM了解很多。可是对pHGG中的TAM和嗜中性粒细胞知之甚少。pHGG更常见于幕下部位就像脑干一样，在成年人的大脑半球之外。pHGG还含有不同的组蛋白在成年人中没有发现的突变。这就提出了一个问题，即pHGG是否拥有一个独特的选区， 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，我们证明了脑干/中线 pHGG（DMG）和鼠弥漫性内在脑桥胶质瘤（DIPG）具有较高的炎症评分，与半球pHGG相比，增加的中性粒细胞评分与较短的患者生存期相关。当仅检查人类半球pHGG时，我们的结果显示了两个患者亚组，炎症评分。炎症评分高的患者的生存时间明显短于炎症评分低的人。我们还表明，人pHGG具有较高的IBA 1+浸润， TAM是pHGG肿瘤微环境（TME）中最丰富的非肿瘤成分。我们的初步数据利用小鼠模型来概括新生免疫活性小鼠中的pHGG，在生物学相关位置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骨髓细胞浸润方面与人类对应物相比。使用 PDGFB和PDGFA作为驱动突变在小鼠中产生半球pHGG，我们能够重述具有高和低炎症评分的人pHGG。我们发现，与PDGFA驱动的肿瘤相比， PDGFB肿瘤具有更高的炎症评分，增加的单核细胞从血液中浸润，以及更短的时间。荷瘤小鼠的存活时间。我们确定CCL 3是CCR 1/CCR 5阳性细胞的潜在关键趋化因子。单核细胞和CXCL 1用于pHGG中CXCR 2阳性中性粒细胞募集。总之，这些结果提供了强有力的理由来扩展我们的研究，以了解特定的组蛋白突变和肿瘤位置如何影响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：（一）揭示 pHGG的髓样区室的分子和功能多样性;（ii）确定髓样区室的不同亚群和骨髓特异性基因影响肿瘤生长和TME;（iii）提供骨髓亚群影响驱动突变、儿科特异性组蛋白突变和肿瘤位置，（半球与脑干）。这项研究还将确定是否靶向单核细胞和中性粒细胞，渗透将是在pHGG中开发的可行的治疗途径。