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Bone marrow-derived myeloid cell dysregulation in malignant progression of glioma

胶质瘤恶性进展中骨髓源性骨髓细胞失调

基本信息

批准号：
10730970
负责人：
Prajwal Rajappa
金额：
$ 47.03万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-15 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10730970
关键词：
Adolescent and Young Adult Affect Automobile Driving Blood Bone Marrow Bone Marrow Cells CD8B1 gene Cell Differentiation process Cell Separation Cells Central Nervous System Neoplasms Circulation Cytometry Data Dependence Flow Cytometry Genes Glioma Goals Human ID2 gene Immunologic Surveillance Immunosuppression Impairment Infiltration Knock-out Macrophage Malignant - descriptor Malignant Glioma Methods Migration Inhibitory Factor Modeling Mus Myelogenous Myeloid Cells Myeloid-derived suppressor cells Natural Killer Cells Outcome Pathway interactions Patients Peripheral Pharmacological Treatment Phenotype Phosphotransferases Population Process Prognosis Risk Role Sampling Signal Transduction Solid Neoplasm Spatial Distribution Spleen T-Lymphocyte Testing Translating Transplantation Treatment Failure Tumor Immunity Tumor Promotion Tumor-associated macrophages Up-Regulation angiogenesis clinically significant differential expression digital experience immune checkpoint immunosuppressive macrophages in vivo insight interest knock-down mouse model mutant novel overexpression peripheral blood prevent receptor single-cell RNA sequencing transcriptome sequencing transcriptomics tumor tumor growth tumor microenvironment

项目摘要

Project Summary Low-grade gliomas (LGGs), a heterogeneous group of primary central nervous system tumors, are one of the most common solid tumors in the adolescent and young adult (AYA) population. LGGs can progress to high- grade gliomas (HGGs) via a process known as malignant transformation (MT), resulting in dismal prognoses. The mechanisms driving MT of LGG remain poorly understood. In contrast to LGGs, we and others have shown that HGGs have increased levels of bone marrow-derived myeloid cells (BMDMs) and myeloid-derived suppressor cells (MDSCs) in peripheral circulation, with an intra-tumoral enrichment of tumor-associated macrophages (TAMs) and a paucity of CD8+T and natural killer (NK) cells. Although myeloid cells are known to accumulate during glioma progression, it remains unclear if these cells have a causal role in driving MT. Central hypothesis: Reductions in anti-tumor reactive CD8+T and NK cell-dependent immune surveillance are responsible for LGG to HGG malignant transformation in AYA patients and these reductions are dictated by increased infiltration and immune suppressive activity of tumor infiltrating BMDMs. We have identified two independent myeloid associated pathways that are responsible for these BMDM phenotypes and we propose to test the central hypothesis through the following two aims: Aim 1. Delineate the dependency of BMDM cell differentiation on inhibitor of DNA binding protein 2 (ID2). Using AYA RCAS/tv-a glioma mouse models, we will knockdown ID2 in BMDMs before and during MT. We will examine effects on pro-tumoral myeloid cells and evaluate intra-tumoral T and NK cells and mobilization in blood, spleen, and bone marrow at various times with scRNAseq, mass cytometry, and fluorescent-activated cell sorting. We will also leverage digital spatial transcriptomics (DSP) in ID2 modulated tumors and validate ID2 signaling in human paired LGG /HGG samples to dissect the expression of myeloid, NK, T cell markers, and checkpoint molecules to illuminate ROIs critical to MT. Results will illuminate ID2 mechanisms of BMDM cell differentiation to pro-tumoral myeloid cells. Aim 2. Determine if the CD74/macrophage migration inhibitory factor (MIF) axis regulates BMDM cell differentiation during LGG malignant transformation. We will investigate CD74’s role in MT using pharmacological treatments or transplant wild-type or CD74 KD/KO bone marrow cells in a murine RCAS/tv-a glioma model. We will analyze peripheral blood and the glioma TME using scRNAseq, mass cytometry, and FACS. We will validate findings with bulk RNA sequencing data on paired LGG/HGGs from AYA patients and investigate how CD74/MIF signaling drives reduced T and NK cells which supports LGG MT. We will also leverage DSP in CD74/MIF modulated tumors and validate CD74 signaling in human paired LGG/HGG samples to dissect the expression of myeloid, NK, T cell markers, and checkpoint molecules to illuminate ROIs critical to MT that will indicate potentially targetable vulnerabilities. Overall Impact: Our studies will illuminate novel insights that may enable us to translate into enhanced immune surveillance approaches to delay and/or prevent MT for AYA LGG patients.

项目总结