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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：
10783846
负责人：
Roarke Alexander Kamber
金额：
$ 24.9万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10783846
关键词：
Address Adipocytes Affect Antibodies Antibody-Dependent Enhancement Antigen Targeting Biochemical Bioinformatics Biological Assay CD47 gene CRISPR screen CRISPR/Cas technology Cancer Etiology Cancer Patient Cell Extracts Cell membrane Cessation of life Clinical Communication Computer Analysis Development Development Plans ERBB2 gene Enabling Factors Environment Enzymes Foundations GPR84 gene Genetic Screening Goals Immune Immune checkpoint inhibitor Immune response Immunocompetent Immunologics Immunotherapy In Vitro Inflammatory Knock-out Knowledge Laboratories Lipids Lymphocyte Lymphocyte Suppression Lymphoma Macrophage Malignant Neoplasms Malignant neoplasm of lung Mediating Medium chain fatty acid Membrane Glycoproteins Membrane Proteins Mentors Mentorship Methods Modeling Molecular Monitor Monoclonal Antibodies Monoclonal Antibody Therapy Mus Natural Killer Cells Outcome Pathway interactions Patient-Focused Outcomes Phagocytes Phagocytosis Phagocytosis Inhibition Phase Prognosis Protein Deficiency Regulation Research Personnel Research Training Resistance Role Series Signal Transduction Testing Therapeutic Therapeutic Monoclonal Antibodies Training Trastuzumab Tumor Antigens Tumor Cell Line Tumor Escape Universities Work adaptive immune response anti-CD20 anti-cancer anti-tumor immune response antibody-dependent cellular phagocytosis cancer cell cancer immunotherapy cancer therapy cancer type career career development experience experimental study fatty acid metabolism functional genomics genome wide screen immune cell infiltrate immune checkpoint improved in vivo innovation lipid metabolism lung cancer cell mouse model neoplastic cell novel novel therapeutics pre-clinical receptor resistance mechanism rituximab skills small cell lung carcinoma standard of care success synergism technique development therapeutic target tumor tumor immunology tumor 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.

项目概要/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，但受到淋巴细胞丰度低和/或抑制的严重阻碍许多癌症的肿瘤微环境。这项工作旨在解决这一重大问题小细胞肺癌 (SCLC) 是所有癌症中预后最差的一种适应性免疫检查点抑制剂在改善患者预后方面取得的成功有限。策略刺激巨噬细胞活性的研究越来越多，因为巨噬细胞构成了高 SCLC 和许多其他癌症中肿瘤细胞总量的百分比。治疗性单克隆抗体（单克隆抗体）可以诱导巨噬细胞通过吞噬作用杀死癌细胞并启动适应性免疫回应。然而，癌细胞表达的抗吞噬因子，仅其中一部分已被证实。确定，能够抵抗吞噬作用。我的长期目标是提高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单克隆抗体功效的治疗途径。我将基于创新的 CRISPR/Cas9 筛选我开发的方法是为了确定调节癌症对吞噬作用敏感性的因素。这种做法揭示了一套已知的和新颖的抗吞噬途径。该提案的目的是调查我发现的最有效的新机制之一，并检验癌细胞的中心假设代谢炎症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通过实验了解癌症来源的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性和适应性使用 SCLC 免疫活性小鼠模型进行抗癌免疫反应。最后，在目标 3 中，我将系统地表征 SCLC 中不同抗吞噬途径之间的协同作用，以揭示脂质如何监管机构和其他因素合作阻止巨噬细胞攻击，这可能表明可能存在新的联合治疗策略。这些相关但独立的目标的预期结果是了解所使用的新型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，以逃避单克隆抗体治疗。这些目标将在恒星内部实现斯坦福大学的科学环境，由经验丰富的团队提供研究培训和指导由功能基因组学、癌症免疫学、脂质信号传导和生物信息学方面的专家组成。职业生涯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、指导和培训方面的专业培训实验室管理，将为我作为一名独立研究者的职业生涯奠定坚实的基础。