Understanding the cellular and functional changes in the immune tumor microenvironment of glioblastoma during progression and treatments.

了解胶质母细胞瘤在进展和治疗过程中免疫肿瘤微环境的细胞和功能变化。

• 批准号: 10681034
• 负责人: VASSILIKI A BOUSSIOTIS
• 金额: $ 67.26万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-17 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681034
• 关键词: Address; Aftercare; Animals; Area; Bone Marrow; CDKN2A gene; Cell Communication; Cell Separation; Cells; Chemotherapy and/or radiation; Clinical; Data Set; Development; Dexamethasone; Epidermal Growth Factor Receptor; Event; Evolution; Experimental Models; Flow Cytometry; Genetically Engineered Mouse; Genomics; Glioblastoma; Glioma; Heterogeneity; Human; Immune; Immunology; Immunosuppression; Immunotherapy; Infiltration; Inflammatory; Institution; International; Ionizing radiation; Knowledge; Lesion; Macrophage; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Maps; Mediating; Microglia; Modality; Molecular; Mouse Strains; Mus; Mutation; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Nature; Output; PTEN gene; Pathology; Pathway interactions; Patient Care; Patients; Population; Population Dynamics; Property; Radiation; Reaction; Research; Resistance; Sampling; Signal Transduction; Spatial Distribution; T-Lymphocyte; Technology; The Cancer Genome Atlas; Therapeutic; Time; Tumor Suppressor Genes; Tumor-infiltrating immune cells; cancer cell; checkpoint inhibition; checkpoint therapy; clinically relevant; clinically significant; design; effective therapy; epidermal growth factor receptor VIII; human data; immune cell infiltrate; immune checkpoint blockade; immune resistance; insight; longitudinal analysis; member; mouse model; multiple omics; multiplexed imaging; mutant; neoplastic; neoplastic cell; new therapeutic target; novel therapeutic intervention; overexpression; pre-clinical; protein biomarkers; recruit; single cell analysis; single-cell RNA sequencing; standard of care; success; targeted treatment; temozolomide; therapeutic development; transcriptome sequencing; transcriptomics; tumor; tumor immunology; tumor-immune system interactions; tumorigenic

Project Summary Glioblastoma (GBM) is an incurable primary malignant brain cancer characterized by a high degree of interpatient and intratumoral genomic and cellular heterogeneity, a brief median survival (~15 months), and absence of an effective treatment. Even the successes of checkpoint blockade immunotherapies observed in many cancers have not translated to GBM. The GBM tumor immune microenvironment (TIME) is highly immunosuppressive and is dominated by resident and infiltrating myeloid cells (30-40% of the tumor mass) compared to rare T cells (<5%). Although recent single-cell RNA-sequencing (scRNAseq) studies have provided broad characterization of the cellular makeup and evolution of GBM tumor cells, dissecting the diversity, function and regional localization of the immune composition of GBM remains incomplete. There is also a widespread lack of knowledge on the evolution of intratumoral immune cells during GBM progression, and throughout treatment with standard of care (SOC) therapies (ionizing radiation/ temozolomide/dexamethasone IR/TMZ/DEX). Major challenges to achieving scientific and clinical impact in GBM remain, including an in-depth understanding of the interactions between cancer cells and the immune microenvironment in the context of SOC and immunotherapy treatments. Such knowledge is difficult to obtain using freshly excised patient samples. The main hypothesis of the proposal is that critical and clinically relevant changes in GBM neoplastic and immune cells brought about by treatment modalities can be revealed using genetically accurate mouse models to parse and redirect analyses of human patient datasets. A mechanistic understanding of the effects of therapies on immune and tumorigenic cell population dynamics in pre-clinical mouse models in combination with analysis of human patient datasets will yield transformative advancements in the field. We will leverage archival patient samples, mouse models of GBM and GLASS consortium datasets to uncover SOC-related cellular and molecular evolutionary changes using scRNA seq and spatial transcriptomics. We will also unveil factors determining sensitivity and resistance to checkpoint blockade therapy. By integrating detailed mouse and human data, we will identify areas of unrecognized therapeutic vulnerabilities and pave the way for the development of new treatment approaches.

项目摘要 胶质母细胞瘤（GBM）是一种无法治愈的原发性恶性脑癌，其特征是高度的 室内和肿瘤内基因组和细胞异质性，短期中位生存期（约15个月），以及 没有有效的治疗方法。甚至在 许多癌症尚未转化为GBM。 GBM肿瘤免疫微环境（时间）高度高 免疫抑制作用，由居民和渗透髓样细胞（占肿瘤质量的30-40％）主导 与罕见的T细胞相比（<5％）。尽管最近的单细胞RNA测序（SCRNASEQ）研究已经 提供了GBM肿瘤细胞的细胞构成和演变的广泛表征，剖析了 GBM免疫组成的多样性，功能和区域定位仍然不完整。有 同样，在GBM进展过程中，人们对肿瘤内免疫细胞的演变的知识也普遍存在， 并在治疗标准（SOC）疗法（电离辐射/ Temozolomide/地塞米松IR/TMZ/DEX）。实现科学和临床影响的主要挑战 保留GBM，包括对癌细胞与免疫之间相互作用的深入了解 在SOC和免疫疗法的背景下的微环境。这样的知识很难获得 使用新鲜切除的患者样品。该提案的主要假设是关键和临床相关 可以使用治疗方式带来的GBM肿瘤和免疫细胞的变化。 遗传准确的小鼠模型分析和重定向人类患者数据集的分析。机械 了解疗法对临床前临床前免疫和致瘤细胞种群动力学的影响 与人类患者数据集的分析结合的鼠标模型将产生变革性的进步 在现场。我们将利用存档患者样本，GBM的鼠标模型和玻璃财团数据集 使用SCRNA SEQ和空间发现与SOC相关的细胞和分子进化变化 转录组学。我们还将揭露确定敏感性和对检查点封锁的敏感性的因素 治疗。通过整合详细的鼠标和人类数据，我们将确定未识别的治疗领域 脆弱性并为开发新治疗方法铺平道路。