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。
基本信息
- 批准号:10681034
- 负责人:
- 金额:$ 67.26万
- 依托单位:
- 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:2023-04-17 至 2028-03-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAftercareAnimalsAreaBone MarrowCDKN2A geneCell CommunicationCell SeparationCellsChemotherapy and/or radiationClinicalData SetDevelopmentDexamethasoneEpidermal Growth Factor ReceptorEventEvolutionExperimental ModelsFlow CytometryGenetically Engineered MouseGenomicsGlioblastomaGliomaHeterogeneityHumanImmuneImmunologyImmunosuppressionImmunotherapyInfiltrationInflammatoryInstitutionInternationalIonizing radiationKnowledgeLesionMacrophageMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of brainMapsMediatingMicrogliaModalityMolecularMouse StrainsMusMutationMyelogenousMyeloid CellsMyeloid-derived suppressor cellsNatureOutputPTEN genePathologyPathway interactionsPatient CarePatientsPopulationPopulation DynamicsPropertyRadiationReactionResearchResistanceSamplingSignal TransductionSpatial DistributionT-LymphocyteTechnologyThe Cancer Genome AtlasTherapeuticTimeTumor Suppressor GenesTumor-infiltrating immune cellscancer cellcheckpoint inhibitioncheckpoint therapyclinically relevantclinically significantdesigneffective therapyepidermal growth factor receptor VIIIhuman dataimmune cell infiltrateimmune checkpoint blockadeimmune resistanceinsightlongitudinal analysismembermouse modelmultiple omicsmultiplexed imagingmutantneoplasticneoplastic cellnew therapeutic targetnovel therapeutic interventionoverexpressionpre-clinicalprotein biomarkersrecruitsingle cell analysissingle-cell RNA sequencingstandard of caresuccesstargeted treatmenttemozolomidetherapeutic developmenttranscriptome sequencingtranscriptomicstumortumor immunologytumor-immune system interactionstumorigenic
项目摘要
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,其特征是高度的恶性胶质瘤。
患者间和肿瘤内基因组和细胞异质性,短暂的中位生存期(约15个月),和
缺乏有效的治疗。即使是检查点阻断免疫疗法的成功,
许多癌症尚未转化为GBM。GBM肿瘤免疫微环境(TIME)是一种高度依赖性的免疫系统。
免疫抑制,主要由常驻和浸润性髓样细胞(占肿瘤质量的30-40%)
与罕见的T细胞相比(<5%)。尽管最近的单细胞RNA测序(scRNAseq)研究
提供了GBM肿瘤细胞的细胞组成和演变的广泛表征,解剖了
GBM的免疫组成的多样性、功能和区域定位仍然不完全。有
还普遍缺乏关于GBM进展期间肿瘤内免疫细胞进化的知识,
以及在整个标准护理(SOC)疗法(电离辐射/放射疗法)治疗期间,
替莫唑胺/地塞米松IR/TMZ/DEX)。实现科学和临床影响的主要挑战
GBM仍然存在,包括对癌细胞与免疫之间相互作用的深入了解
在SOC和免疫疗法治疗的背景下的微环境。这样的知识很难获得
使用新鲜切除的患者样本。该提案的主要假设是,
治疗方式引起的GBM肿瘤细胞和免疫细胞的变化可以通过使用
遗传上精确的小鼠模型来解析和重定向人类患者数据集的分析。一种机械的
了解临床前治疗对免疫和致瘤细胞群体动态的影响
小鼠模型与人类患者数据集的分析相结合将产生变革性的进步
在外地我们将利用存档的患者样本、GBM小鼠模型和GLASS联盟数据集
使用scRNA序列和空间分析技术揭示SOC相关的细胞和分子进化变化,
转录组学我们还将揭示决定对检查站封锁的敏感性和抵抗力的因素
疗法通过整合详细的小鼠和人类数据,我们将确定未被识别的治疗领域,
这将有助于消除脆弱性,并为开发新的治疗方法铺平道路。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('VASSILIKI A BOUSSIOTIS', 18)}}的其他基金
Detection of PD-1 inhibitory signaling and its molecular relays in T cells: Implications for cancer immunotherapy
T 细胞中 PD-1 抑制信号传导及其分子中继的检测:对癌症免疫治疗的影响
- 批准号:
10605878 - 财政年份:2023
- 资助金额:
$ 67.26万 - 项目类别:
The effects of PD-1 on tumor-mediated “emergency” myelopoiesis and fate commitment of myeloid cells: Implications for anti-tumor immunity
PD-1 对肿瘤介导的“紧急”骨髓生成和骨髓细胞命运决定的影响:抗肿瘤免疫的意义
- 批准号:
10330481 - 财政年份:2020
- 资助金额:
$ 67.26万 - 项目类别:
The effects of PD-1 on tumor-mediated “emergency” myelopoiesis and fate commitment of myeloid cells: Implications for anti-tumor immunity
PD-1 对肿瘤介导的“紧急”骨髓生成和骨髓细胞命运决定的影响:抗肿瘤免疫的意义
- 批准号:
10547788 - 财政年份:2020
- 资助金额:
$ 67.26万 - 项目类别:
Advancing treatment outcomes in malignant glioma by integrating immunotherapy and standard of care using genetically engineered mice that recapitulate molecular feature of human glioma
通过使用重现人类神经胶质瘤分子特征的基因工程小鼠整合免疫疗法和护理标准来提高恶性神经胶质瘤的治疗效果
- 批准号:
10524100 - 财政年份:2018
- 资助金额:
$ 67.26万 - 项目类别:
Advancing treatment outcomes in malignant glioma by integrating immunotherapy and standard of care using genetically engineered mice that recapitulate molecular feature of human glioma
通过使用重现人类神经胶质瘤分子特征的基因工程小鼠整合免疫疗法和护理标准来提高恶性神经胶质瘤的治疗效果
- 批准号:
10198866 - 财政年份:2018
- 资助金额:
$ 67.26万 - 项目类别:
Advancing treatment outcomes in malignant glioma by integrating immunotherapy and standard of care using genetically engineered mice that recapitulate molecular feature of human glioma
通过使用重现人类神经胶质瘤分子特征的基因工程小鼠整合免疫疗法和护理标准来提高恶性神经胶质瘤的治疗效果
- 批准号:
10431932 - 财政年份:2018
- 资助金额:
$ 67.26万 - 项目类别:
Advancing Treatment Outcomes in Malignant Glioma by Integrating Immunotherapy and Standard of Care using Genetically Engineered Mice that Recapitulate Molecular Feature of Human Glioma
通过使用重现人类胶质瘤分子特征的基因工程小鼠整合免疫疗法和护理标准来提高恶性胶质瘤的治疗效果
- 批准号:
10377182 - 财政年份:2018
- 资助金额:
$ 67.26万 - 项目类别:
Improving anti-tumor T cell immunity by targeting LDH-A functions beyond the Warburg effect
通过超越 Warburg 效应靶向 LDH-A 功能来提高抗肿瘤 T 细胞免疫力
- 批准号:
9919516 - 财政年份:2017
- 资助金额:
$ 67.26万 - 项目类别:
Improving anti-tumor T cell immunity by targeting LDH-A functions beyond the Warburg effect
通过超越 Warburg 效应靶向 LDH-A 功能来提高抗肿瘤 T 细胞免疫力
- 批准号:
10152529 - 财政年份:2017
- 资助金额:
$ 67.26万 - 项目类别:
Effects of PGE2 on Reconstitution of Hematopoiesis and Immunity after UCBT
PGE2对UCBT后造血和免疫重建的影响
- 批准号:
8985871 - 财政年份:2013
- 资助金额:
$ 67.26万 - 项目类别:
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