Systematic Discovery and Characterization of Novel Cancer Anti-Phagocytic Mechanisms
新型癌症抗吞噬机制的系统发现和表征
基本信息
- 批准号:10370993
- 负责人:
- 金额:$ 11.99万
- 依托单位:
- 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:2022-03-15 至 2024-02-28
- 项目状态:已结题
- 来源:
- 关键词:AddressAdipocytesAffectAntibodiesAntibody-Dependent EnhancementAntigen TargetingBiochemicalBioinformaticsBiological AssayCD47 geneCRISPR screenCRISPR/Cas technologyCancer EtiologyCancer PatientCell ExtractsCell membraneCessation of lifeClinicalCommunicationComputer AnalysisDevelopmentDevelopment PlansERBB2 geneEnvironmentEnzymesFoundationsGPR84 geneGenetic ScreeningGoalsImmuneImmune checkpoint inhibitorImmune responseImmunocompetentImmunologicsImmunotherapyIn VitroInflammatoryKnock-outKnowledgeLaboratoriesLipidsLymphocyteLymphocyte SuppressionLymphomaMalignant NeoplasmsMalignant neoplasm of lungMediatingMedium chain fatty acidMembrane GlycoproteinsMembrane ProteinsMentorsMentorshipMethodsModelingMolecularMonitorMonoclonal AntibodiesMonoclonal Antibody TherapyMusNatural Killer CellsOutcomePathway interactionsPatient-Focused OutcomesPhagocytesPhagocytosisPhasePrognosisProtein DeficiencyRegulationResearch PersonnelResearch TrainingResistanceRoleSeriesSignal TransductionTestingTherapeuticTherapeutic Monoclonal AntibodiesTrainingTrastuzumabTumor AntigensTumor Cell LineTumor-infiltrating immune cellsUniversitiesWorkadaptive immune responseanti-CD20anti-canceranti-tumor immune responseantibody-dependent cellular phagocytosisbasecancer cellcancer immunotherapycancer therapycancer typecareercareer developmentexperienceexperimental studyfatty acid metabolismfunctional genomicsgenome wide screenimmune checkpointimprovedin vivoinnovationlipid metabolismlung cancer celllung small cell carcinomamacrophagemouse modelneoplastic cellnovelnovel therapeuticspre-clinicalreceptorresistance mechanismrituximabskillsstandard of caresuccesssynergismtechnique developmenttherapeutic targettumortumor immunologytumor microenvironment
项目摘要
Project Summary/Abstract
Recent strategies to stimulate anti-cancer immune responses have transformed treatment options for many
cancer patients, but are critically hindered by the low abundance and/or suppression of lymphocytes in the
tumor microenvironment of many cancers. This work aims to address this significant problem in the context
of small cell lung cancer (SCLC), which has among the worst prognoses among all cancers and for which
adaptive immune checkpoint inhibitors have shown limited success in improving patient outcomes. Strategies
to stimulate macrophage activity are increasingly being investigated, as macrophages constitute a high
percentage of total tumor cell mass in SCLC and many other cancers. Therapeutic monoclonal antibodies
(mAbs) can induce macrophages to both kill cancer cells via phagocytosis and to prime adaptive immune
responses. However, anti-phagocytic factors expressed by cancer cells, only some of which have been
identified, enable resistance to phagocytosis. My long-term goal is to advance our fundamental knowledge
of the mechanisms by which cancer cells evade antibody-dependent phagocytosis, which might create new
therapeutic avenues to enhance mAb efficacy. I will build on an innovative CRISPR/Cas9-screening
approach I have developed to identify factors that modulate cancer sensitivity to phagocytosis. This approach
revealed a suite of known and novel anti-phagocytic pathways. The objective of this proposal is to investigate
one of the most potent novel mechanisms I identified, and to test the central hypothesis that cancer cells
metabolize inflammatory lipids to avoid activating macrophages. In Aim 1, I will undertake a series of in vitro
experiments to understand the mechanistic basis of macrophage regulation by cancer-derived
immunostimulatory lipids. In Aim 2, I will determine how cancer lipid regulation affects innate and adaptive
anti-cancer immune responses using an immunocompetent mouse model for SCLC. Finally, in Aim 3, I will
systematically characterize synergies between diverse anti-phagocytic pathways in SCLC to reveal how lipid
regulators and other factors cooperate to block macrophage attack, which may suggest possible new
combination therapeutic strategies. The expected outcome of these related but independent aims is an
understanding of the molecular mechanisms of a novel immunosuppressive lipid metabolism pathway used
by diverse cancers, including SCLC, to evade mAb therapies. These aims will be pursued within the stellar
scientific environment of Stanford University, with research training and mentorship by an experienced team
of experts in functional genomics, cancer immunology, lipid signaling, and bioinformatics. The career
development plan involves research training in lipid analysis methods, mouse tumor models, and
computational analysis of genetic screens, as well as professional training in communication, mentoring, and
laboratory management, and will establish a strong foundation for my career as an independent investigator.
项目总结/摘要
最近刺激抗癌免疫反应的策略已经改变了许多人的治疗选择,
癌症患者,但严重阻碍了低丰度和/或抑制淋巴细胞中的
许多癌症的肿瘤微环境。这项工作旨在解决这一重大问题的背景下,
小细胞肺癌(SCLC)是所有癌症中最严重的一种,
适应性免疫检查点抑制剂在改善患者结果方面显示出有限的成功。战略
由于巨噬细胞占很高的比例,刺激巨噬细胞活性的研究越来越多,
在SCLC和许多其他癌症中占总肿瘤细胞质量的百分比。治疗性单克隆抗体
单克隆抗体(mAb)可以诱导巨噬细胞通过吞噬作用杀死癌细胞,并引发适应性免疫
应答然而,癌细胞表达的抗吞噬因子,其中只有一些已经被发现。
识别,使抵抗吞噬作用。我的长期目标是推进我们的基础知识
癌细胞逃避抗体依赖性吞噬作用的机制,这可能会创造新的
增强mAb功效的治疗途径。我将建立一个创新的CRISPR/Cas9筛选
我已经开发了一种方法来确定调节癌症对吞噬作用敏感性的因素。这种方法
揭示了一套已知的和新的抗吞噬途径。本提案的目的是调查
这是我发现的最有效的新机制之一,为了验证癌细胞
代谢炎性脂质以避免激活巨噬细胞。在目标1中,我将进行一系列体外
实验以了解巨噬细胞调节的机制基础,
免疫刺激脂质。在目标2中,我将确定癌症脂质调节如何影响先天和适应性
使用SCLC的免疫活性小鼠模型的抗癌免疫应答。最后,在目标3中,我将
系统地表征SCLC中不同抗吞噬细胞途径之间协同作用,以揭示脂质
调节因子和其他因子合作阻止巨噬细胞的攻击,这可能表明可能的新的
联合治疗策略。这些相关但独立的目标的预期结果是
了解一种新的免疫抑制脂质代谢途径的分子机制,
包括SCLC在内的多种癌症,以逃避mAb治疗。这些目标将在恒星内部实现。
斯坦福大学的科学环境,由经验丰富的团队进行研究培训和指导
功能基因组学、癌症免疫学、脂质信号传导和生物信息学方面的专家。职业
发展计划包括脂质分析方法、小鼠肿瘤模型和
遗传筛选的计算分析,以及沟通,指导和
实验室管理,并将建立一个强大的基础,我的职业生涯作为一个独立的调查员。
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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Roarke Alexander Kamber其他文献
Roarke Alexander Kamber的其他文献
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{{ truncateString('Roarke Alexander Kamber', 18)}}的其他基金
Deciphering a novel lipid-based mechanism of innate immune modulation
破译一种新型的基于脂质的先天免疫调节机制
- 批准号:
10726010 - 财政年份:2023
- 资助金额:
$ 11.99万 - 项目类别:
Systematic Discovery and Characterization of Novel Cancer Anti-Phagocytic Mechanisms
新型癌症抗吞噬机制的系统发现和表征
- 批准号:
10783846 - 财政年份:2022
- 资助金额:
$ 11.99万 - 项目类别:
Systematic Discovery and Characterization of Novel Cancer Anti-Phagocytic Mechanisms
新型癌症抗吞噬机制的系统发现和表征
- 批准号:
10591608 - 财政年份:2022
- 资助金额:
$ 11.99万 - 项目类别:
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- 项目类别:面上项目
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