Regulation of the innate immune response in the tumor microenvironment of lung adenocarcinoma

在美国，肺癌比任何其他形式的癌症造成更多的死亡。不幸的是， 许多肺癌患者对有效动员细胞毒性T细胞对抗肺癌的治疗没有反应。 其他癌症中的肿瘤（例如抗PD-1/PD-L1和抗CTLA 4）。这种对肺癌缺乏反应的现象 主要是由于不能启动强有力的抗肿瘤免疫应答。肺癌细胞分泌 损伤相关分子模式蛋白，高迁移率族蛋白1（HMGB 1），其具有双重功能 豁免权。虽然它可以促进免疫细胞浸润到肿瘤中，但它的主要功能是驱动免疫细胞浸润到肿瘤中。 分泌负性免疫调节剂，包括TGF-β和IL-10，并增加程序性 死亡受体配体1（PD-L1）。我的初步数据表明，单不饱和脂肪酸（MUFA） 这是阻止HMGB 1从肺癌细胞分泌所必需的。因此，我假设肺癌患者 肿瘤相关MUFA浓度越低，HMGB 1表达越高， 免疫抑制肿瘤微环境（TME）。为了验证这一假设，我提出了两个具体目标：1） 确定患者中MUFA、细胞外HMGB 1和肺癌之间的相关性; 2）评估MUFA、细胞外HMGB 1和肺癌之间的相关性。 MUFA对体外肿瘤HMGB 1分泌及癌相关成纤维细胞活化的影响 模型我将使用脂质组学和免疫学测定来确定MUFA与 肺癌患者分泌HMGB 1。使用患者组织外植体，我将测量 MUFA对HMGB 1分泌的药理学抑制。研究基因和药理学的影响 抑制MUFA对TME的影响，我将构建血管化的三维生物打印肺肿瘤 使用肺癌细胞和肺成纤维细胞。这将允许表征免疫调节细胞因子 由癌症相关的成纤维细胞分泌，这是肺肿瘤中的主要细胞类型。长期目标是 研究的目的是深入了解肿瘤协调免疫抑制的机制， 使我们能够开发新的策略来克服这种免疫屏障。K 01提案是 旨在建立在我的培训背景和基本分子和癌症生物学的记录， 扩展我作为翻译研究员的技能我的科学顾问委员会是由 具有肿瘤学、肺病、脂质生物化学、成纤维细胞生物学和 分子生物学K 01提案中概述的计划将推动我成为一名独立的科学家。 职业生涯通过严格的职业发展活动量身定制我的具体研究目标。

Lung cancer is responsible for more deaths in the United States than any other form of cancer. Unfortunately, many lung cancer patients do not respond to treatments that effectively mobilize cytotoxic T cells against tumors in other cancers (e.g. anti-PD-1/PD-L1 and anti-CTLA4). This lack of response in lung cancer is primarily due to an inability to initiate a robust antitumor immune response. Lung cancer cells secrete the damage-associated molecular pattern protein, High Mobility Group Box 1 (HMGB1) which has a dual function in immunity. Although it can facilitate immune cell infiltration into tumors; its predominant function is to drive the secretion of negative immune regulators including TGF-b and IL-10 and increase expression of programmed death receptor ligand 1 (PD-L1). My preliminary data suggest that monounsaturated fatty acids (MUFA) are required to prevent HMGB1 secretion from lung cancer cells. Therefore, I hypothesize that lung cancer patients with lower concentrations of tumor-associated MUFA will have higher expression of HMGB1 resulting in an immunosuppressive tumor microenvironment (TME). To test this hypothesis, I propose two Specific Aims: 1) Determine the association between MUFA, extracellular HMGB1, and lung cancer in patients; 2) Evaluate the effects of MUFA on secretion of HMGB1 and the activation of cancer-associated fibroblasts in ex vivo tumor models. I will use lipidomic and immunological assays to determine the association between MUFA and secreted HMGB1 in lung cancer patients. Using patient tissue explants, I will measure the effects of pharmacologic inhibition of MUFA on secretion of HMGB1. To study the effects of genetic and pharmacologic inhibition of MUFA on the TME, I will construct vascularized 3-dimensional bioprinted lung tumors constructed using lung cancer cells and lung fibroblasts. This will allow characterization of immune modulating cytokines secreted by cancer-associated fibroblasts, a dominant cell type within lung tumors. The long-term goal of this research is to provide insight into the mechanisms by which tumors orchestrate immune suppression, and enable the development of new strategies to overcome this immunological barrier. This K01 proposal is designed to build upon my training background and track record in basic molecular and cancer biology, and expand my skills as a translational researcher. My scientific advisory committee is composed of accomplished scientists and clinicians with expertise in oncology, lung disease, lipid biochemistry, fibroblast biology and molecular biology. The program outlined in this K01 proposal will propel me into an independent scientific career through rigorous career development activities tailored to my specific research goals.