Cancer-Cell and T-cell Dependent Regulation of Tumor Associated Macrophages
肿瘤相关巨噬细胞的癌细胞和 T 细胞依赖性调节
基本信息
- 批准号:10015239
- 负责人:
- 金额:$ 19.82万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-10 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:Academic Medical CentersAdaptive Immune SystemAddressAdvisory CommitteesAnti-Inflammatory AgentsAntibodiesAntigen PresentationAntigensAntitumor ResponseAutoimmunityAwardBlood VesselsCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCD8B1 geneCDKN2A geneCTLA4 geneCancer EtiologyCancer VaccinesCell divisionCellsCharacteristicsClinicalComputational BiologyCytometryCytotoxic ChemotherapyDNA Sequence AlterationDendritic CellsDevelopmentDisseminated Malignant NeoplasmEnvironmentGenetic TranscriptionGenetically Engineered MouseGenomic InstabilityGoalsGranulocytic SarcomaGrowthGrowth FactorHematologyHistocompatibility Antigens Class IIHomeostasisHyperplasiaImmune TargetingImmune responseImmune systemImmunogenomicsImmunologicsImmunologyImmunosuppressionImmunotherapeutic agentImmunotherapyInduced MutationInfiltrationInflammatoryInterferonsInternal MedicineInvestigationLaboratoriesLeadLesionLungLung AdenocarcinomaMalignant NeoplasmsMalignant neoplasm of lungMalignant neoplasm of thoraxMediatingMedical OncologyMentorsMethylcholanthreneModelingMolecular ProfilingMonoclonal AntibodiesMusMutationMyelogenousMyeloid CellsMyeloid-derived suppressor cellsNon-Small-Cell Lung CarcinomaOncogenicOncologyPatient CarePatientsPeptidesPhenotypePhysiciansPlayPopulationPrincipal InvestigatorProgram DevelopmentProteinsRegimenRegulationResearch PersonnelResearch Project GrantsResolutionRoleSTK11 geneScientistSignal TransductionSurfaceT cell responseT-Cell ActivationT-LymphocyteTestingTissuesTrainingTransplantationTreatment EfficacyTumor ImmunityTumor-Infiltrating LymphocytesTumor-associated macrophagesUniversitiesVocational GuidanceWashingtonWorkadenomaanti-CTLA4anti-PD-1anti-tumor immune responsebak proteincancer cellcancer immunobiologycancer immunotherapycareer developmentcell transformationcell typecheckpoint therapyclinically relevantcytokinedimensional analysisearly phase clinical trialeffector T cellexhaustionexperiencegenetic regulatory proteinhigh dimensionalityhuman modelimmune checkpointimprovedindividual patientlongitudinal analysislung developmentmacrophagemetaplastic cell transformationmonocytemortalitymouse modelneoantigensneoplastic cellnovelpathogenpatient subsetspreventprogrammed cell death protein 1recruitresponsesarcomasingle-cell RNA sequencingskillstherapy resistanttumortumor growthtumor microenvironment
项目摘要
PROJECT SUMMARY/ABSTRACT
The long-term goal of this proposal is to train the applicant to become an independent, academic physician-
scientist studying natural and therapeutic immune responses against lung cancer. The principal investigator
(PI) has previously obtained Ph.D training in immunology, as well as clinical training in internal medicine and
hematology/oncology. He is ABIM board-certified in medical oncology. This application describes a 5-year
career development program that will provide the PI a mentored educational experience with the aim of
developing new scientific expertise in molecular profiling, high-dimensional analysis, computational biology,
and mouse models of human lung adenocarcinoma. At the conclusion of the award period, the PI will have
acquired the skills necessary to achieve his ultimate goal of becoming an independent investigator in a
academic medical center studying lung cancer immunobiology and immunotherapy, and caring for patients
with thoracic malignancies. This research project will capitalize on the expertise and environment of
Washington University, which has a long-track record of developing and supporting physician-scientists. Dr.
Robert D. Schreiber will mentor the PI's scientific and career development. Dr. Schreiber's work is responsible
for the “immunoediting hypothesis” as well as the demonstration that an immunogenomics approach is able to
identify cancer neoantigens, altered proteins resulting from the genomic instability characteristic of malignancy,
and use them as a basis for effective personalized cancer vaccines. An advisory committee of scientists will
provide additional scientific and career guidance. Lung cancer is the most common cause of cancer-related
mortality worldwide. Novel immunotherapy approaches are beneficial for a subset of patients with metastatic
lung adenocarcinoma (LUAD), the most common subtype of non-small cell lung cancer, but responses are
often not durable. The tissue microenvironment of LUAD is characterized by lineages of tumor-associated
macrophages (TAM), which suppress T-cell responses. Our laboratory has demonstrated that TAM display a
spectrum of activation states ranging from a predominantly anti-inflammatory phenotype in progressively
growing tumors to a predominantly pro-inflammatory phenotype in tumors that respond to immunotherapy
treatment. In this proposal, we will test the hypothesis that both T-cell dependent and tumor cell-intrinsic
signals are required for TAM recruitment into the LUAD microenvironment, and that cancer neoantigens
presented by TAM determine the intratumoral function of T-cells mobilized by cancer immunotherapies. For
these studies, we will utilize a genetically engineered mouse model of human LUAD that expresses cancer
neoantigens previously identified and characterized by our laboratory. This allows us to assess immune
responses against both early stage and metastatic cancers. The identification of the precise populations of
TAM that constrain anti-tumoral immune responses will have clinically relevant implications with respect to the
development of novel immunotherapies for patients with non-small cell lung cancer.
项目概要/摘要
该提案的长期目标是培训申请人成为一名独立的、学术型的医生——
研究肺癌自然和免疫治疗反应的科学家。
(PI)之前已获得免疫学博士学位培训以及内科和临床医学培训
他获得了 ABIM 委员会的医学肿瘤学认证。该申请描述了 5 年的临床经验。
职业发展计划将为 PI 提供受指导的教育经验,目的是
发展分子谱分析、高维分析、计算生物学等方面的新科学专业知识,
奖励期结束时,PI 将获得人类肺腺癌的小鼠模型。
获得了实现成为一名独立调查员的最终目标所需的技能
研究肺癌免疫生物学和免疫治疗并照顾患者的学术医疗中心
该研究项目将利用胸部恶性肿瘤的专业知识和环境。
华盛顿大学在培养和支持医学科学家方面有着悠久的历史。
Robert D. Schreiber 将负责指导 PI 的科学和职业发展工作。
表彰“免疫编辑假说”以及免疫基因组学方法能够
识别癌症新抗原,即由恶性肿瘤的基因组不稳定性特征产生的蛋白质,
一个由科学家组成的咨询委员会将利用它们作为有效的个性化癌症疫苗的基础。
提供额外的科学和职业指导 肺癌是癌症相关的最常见原因。
新型免疫治疗方法对部分转移性患者有益。
肺腺癌(LUAD)是非小细胞肺癌最常见的亚型,但反应是
LUAD 的组织微环境通常不持久。
巨噬细胞 (TAM),可抑制 T 细胞反应,我们的实验室已证明 TAM 显示出一种
一系列激活状态,范围从主要的抗炎表型到逐渐的
使肿瘤生长至对免疫治疗有反应的肿瘤中以促炎性表型为主
在本提案中,我们将检验 T 细胞依赖性和肿瘤细胞固有的假设。
TAM 招募到 LUAD 微环境中需要信号,并且癌症新抗原
TAM 提出的方法可确定癌症免疫疗法动员的 T 细胞的瘤内功能。
在这些研究中,我们将利用表达癌症的人类 LUAD 基因工程小鼠模型
我们的实验室先前鉴定和表征了新抗原,这使我们能够评估免疫。
针对早期和转移性癌症的反应 确定准确的人群。
限制抗肿瘤免疫反应的 TAM 将在以下方面产生临床相关影响:
为非小细胞肺癌患者开发新型免疫疗法。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Jeffrey P Ward其他文献
Jeffrey P Ward的其他文献
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{{ truncateString('Jeffrey P Ward', 18)}}的其他基金
Cancer-Cell and T-cell Dependent Regulation of Tumor Associated Macrophages
肿瘤相关巨噬细胞的癌细胞和 T 细胞依赖性调节
- 批准号:
10247683 - 财政年份:2019
- 资助金额:
$ 19.82万 - 项目类别:
Supplement: Cancer-Cell and T-cell Dependent Regulation of Tumor Associated Macrophages
补充:肿瘤相关巨噬细胞的癌细胞和 T 细胞依赖性调节
- 批准号:
10277178 - 财政年份:2019
- 资助金额:
$ 19.82万 - 项目类别:
Cancer-Cell and T-cell Dependent Regulation of Tumor Associated Macrophages
肿瘤相关巨噬细胞的癌细胞和 T 细胞依赖性调节
- 批准号:
10683723 - 财政年份:2019
- 资助金额:
$ 19.82万 - 项目类别:
Cancer-Cell and T-cell Dependent Regulation of Tumor Associated Macrophages
肿瘤相关巨噬细胞的癌细胞和 T 细胞依赖性调节
- 批准号:
10475671 - 财政年份:2019
- 资助金额:
$ 19.82万 - 项目类别:
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