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

在美国，肺癌是导致死亡人数最多的癌症。不幸的是， 许多肺癌患者对有效动员细胞毒性T细胞对抗 其他肿瘤(如抗PD-1/PD-L1和抗CTLA4)。肺癌的这种缺乏反应是 主要是由于无法启动强大的抗肿瘤免疫反应。肺癌细胞分泌 具有双重功能的损伤相关分子模式蛋白高迁移率族蛋白1 在豁免权方面。虽然它可以促进免疫细胞向肿瘤的渗透，但其主要功能是推动 转化生长因子-β、白介素10等免疫负性调节因子的分泌及程序化表达的增加 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) 以防止肺癌细胞分泌HMGB1。因此，我假设肺癌患者 随着肿瘤相关MUFA浓度的降低，HMGB1的表达会更高，从而导致 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MUFA、细胞外HMGB1与患者肺癌的相关性；2)评估 MUFA对体外肿瘤HMGB1分泌及肿瘤相关成纤维细胞活化的影响 模特们。我将使用脂类和免疫学分析来确定MUFA和 肺癌患者分泌HMGB1。使用患者的组织外植体，我将测量 MUFA对HMGB1分泌的药理抑制作用研究遗传和药理学的影响 MUFA对TME的抑制作用，I将构建带血管的三维生物印迹肺肿瘤 使用肺癌细胞和肺成纤维细胞。这将有助于确定免疫调节细胞因子的特征。 由癌症相关的成纤维细胞分泌，这是肺癌中的一种主要细胞类型。这样做的长期目标是 研究是为了深入了解肿瘤协调免疫抑制的机制，以及 能够开发新的策略来克服这一免疫障碍。这份K01提案是 旨在加强我在基础分子和癌症生物学方面的培训背景和记录，以及 拓展我作为翻译研究人员的技能。我的科学顾问委员会是由有成就的 具有肿瘤学、肺部疾病、脂质生物化学、成纤维细胞生物学和 分子生物学。这份K01提案中概述的计划将推动我成为一名独立的科学 通过严格的职业发展活动为我的特定研究目标量身定做。

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.