Systematic Discovery and Characterization of Novel Cancer Anti-Phagocytic Mechanisms

项目摘要/摘要 最近刺激抗癌免疫反应的策略改变了许多人的治疗选择 癌症患者，但严重阻碍了淋巴细胞的低丰度和/或抑制 多种癌症的肿瘤微环境。这项工作旨在解决这一背景下的重大问题 小细胞肺癌(SCLC)是所有癌症中预后最差的癌症之一，对于 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 在小细胞肺癌和许多其他癌症中占总肿瘤细胞质量的百分比。治疗性单抗 (单抗)可诱导巨噬细胞吞噬杀伤癌细胞，并启动获得性免疫。 回应。然而，由癌细胞表达的抗吞噬因子，其中只有一些已经被 经鉴定，可抵抗吞噬作用。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的吞噬作用的机制，这可能会产生新的 提高单抗疗效的治疗途径。我将以创新的CRISPR/CAS9-Screen为基础 方法I已开发用于确定调节癌症对吞噬的敏感性的因素。这种方法 揭示了一套已知的和新的反吞噬途径。这项提议的目的是调查 我发现的最有效的新机制之一，是为了测试癌细胞的中心假设 代谢炎性脂质，避免激活巨噬细胞。在目标1中，我将进行一系列的体外试验 肿瘤来源巨噬细胞调节机制的实验研究 免疫刺激性脂类。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。 使用小细胞肺癌免疫活性小鼠模型的抗癌免疫反应。最后，在《目标3》中，我将 系统地表征小细胞肺癌不同抗吞噬途径之间的协同作用，以揭示脂质是如何 监管机构和其他因素合作阻止巨噬细胞攻击，这可能表明可能有新的 综合治疗策略。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代谢途径的分子机制 包括小细胞肺癌在内的多种癌症，以逃避单抗治疗。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 由功能基因组学、癌症免疫学、脂质信号和生物信息学专家组成。职业生涯 发展计划包括脂类分析方法、小鼠肿瘤模型和 基因筛查的计算分析，以及沟通、指导和专业培训 并将为我作为一名独立调查员的职业生涯奠定坚实的基础。

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.