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：
10591608
负责人：
Roarke Alexander Kamber
金额：
$ 11.99万
依托单位：
STANFORD UNIVERSITY
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 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10591608
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.

项目摘要/摘要刺激抗癌免疫反应的最新策略已改变了许多人的治疗选择癌症患者，但受到低丰度和/或抑制淋巴细胞的严重阻碍许多癌症的肿瘤微环境。这项工作旨在在上下文中解决这个重大问题小细胞肺癌（SCLC），在所有癌症中都有最糟糕的预后自适应免疫检查点抑制剂在改善患者预后方面的成功有限。策略刺激巨噬细胞活性正在越来越多地研究，因为巨噬细胞构成高 SCLC和许多其他癌症中肿瘤细胞总质量的百分比。治疗性单克隆抗体（mAB）可以通过吞噬作用诱导巨噬细胞杀死癌细胞，又可以诱导巨噬细胞。回答。但是，癌细胞表达的抗吞噬因素，其中一些是鉴定出来，可以抵抗吞噬作用。我的长期目标是促进我们的基本知识癌细胞逃避抗体依赖性吞噬作用的机制，这可能会产生新的治疗途径，以增强mAb功效。我将以创新的CRISPR/CAS9筛选为基础我开发的方法是为了识别调节癌细胞增多症敏感性的因素。这种方法揭示了一系列已知和新颖的抗细胞途径。该提议的目的是调查我确定的最有效的新型机制之一，并检验了癌细胞的中心假设代谢炎症性脂质以避免激活巨噬细胞。在AIM 1中，我将进行一系列体外实验了解巨噬细胞调节的机理基础免疫刺激性脂质。在AIM 2中，我将确定癌症脂质调节如何影响先天和适应性 SCLC使用免疫能力的小鼠模型的抗癌免疫反应。最后，在AIM 3中，我会系统地表征SCLC中各种抗吞噬途径之间的协同作用，以揭示脂质的方式监管机构和其他因素合作以阻止巨噬细胞攻击，这可能表明可能是新的结合治疗策略。这些相关但独立目标的预期结果是了解新型免疫抑制脂质代谢途径的分子机制通过包括SCLC在内的各种癌症来逃避mAb疗法。这些目标将在恒星中追求斯坦福大学的科学环境，通过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专家的专家。职业开发计划涉及脂质分析方法，小鼠肿瘤模型和遗传筛查的计算分析，以及在交流，指导和实验室管理，并将为我作为独立调查员的职业建立坚实的基础。