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

肺腺癌肿瘤微环境中先天免疫反应的调节

• 批准号: 10456681
• 负责人: Glenn Edward Simmons
• 金额: $ 15.25万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10456681
• 关键词: 3-Dimensional; Advisory Committees; Biological Response Modifiers; Biology; Blood Vessels; Blood specimen; Cancer Biology; Cancer Etiology; Cancer Patient; Cells; Cessation of life; Cytotoxic T-Lymphocytes; Data; Defense Mechanisms; Development; Disease; Environment; Enzymes; Failure; Fibroblasts; Genetic; Goals; HMGB1 Protein; Immune; Immune checkpoint inhibitor; Immune response; Immunity; Immunologics; Immunology procedure; Immunosuppression; Immunotherapy; Infiltration; Inflammation; Innate Immune Response; Interleukin-10; Learning; Ligands; Lipid Biochemistry; Lipids; Lung; Lung Adenocarcinoma; Lung Neoplasms; Lung diseases; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mediating; Mentors; Minnesota; Modeling; Molecular; Molecular Biology; Monounsaturated Fatty Acids; Natural Immunity; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; Oncology; Patient Care; Patients; Pattern; Pharmacology; Population; Proteins; Refractory Disease; Regulation; Regulatory T-Lymphocyte; Research; Research Personnel; Role; SIRT1 gene; Scientist; Serum; Signal Transduction; Testing; Therapeutic; Tissues; Training; Transforming Growth Factor beta; Translating; Tumor Immunity; United States; Universities; Work; advanced disease; anti-CTLA4; anti-PD-1; anti-tumor immune response; base; biobank; bioprinting; cancer therapy; career; career development; cell type; cytokine; desaturase; design; extracellular; immunogenicity; immunoregulation; improved; inhibitor; innovation; insight; lipidomics; lung cancer cell; melanoma; mortality; prevent; programmed cell death protein 1; programs; receptor; response; skills; success; translational cancer research; translational scientist; treatment response; tumor; tumor microenvironment; tumor-immune system interactions

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.

肺癌在美国造成的死亡人数比任何其他形式的癌症都多。很遗憾， 许多肺癌患者对有效动员细胞毒性T细胞反对的治疗没有反应 其他癌症中的肿瘤（例如抗PD-1/PD-L1和抗CTLA4）。肺癌缺乏反应是 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 损伤相关的分子模式蛋白，高迁移率组框1（HMGB1），具有双功能 免疫。尽管它可以促进免疫细胞浸润到肿瘤中；它的主要功能是驱动 分泌负免疫调节剂，包括TGF-B和IL-10，并增加编程的表达 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）是 预防肺癌细胞中HMGB1分泌所需。因此，我假设肺癌患者 与肿瘤相关的MUFA浓度较低的HMGB1表达较高，导致 免疫抑制肿瘤微环境（TME）。为了检验这一假设，我提出了两个具体目标：1） 确定患者MUFA，细胞外HMGB1和肺癌之间的关联； 2）评估 MUFA对HMGB1分泌的影响和在体内肿瘤中与癌症相关的成纤维细胞的激活 型号。我将使用脂肪组和免疫学测定来确定MUFA和 肺癌患者的分泌HMGB1。使用患者组织外植体，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 抑制MUFA在TME上，我将构建构建的血管化3维生物打印肺肿瘤 使用肺癌细胞和肺成纤维细胞。这将允许体征免疫调节细胞因子 由癌症相关的成纤维细胞分泌，这是肺部肿瘤中的主要细胞类型。这个长期目标 研究是为了洞悉肿瘤来协调免疫抑制的机制以及 使新策略的制定能够克服这种免疫障碍。这个K01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往绩之上，以及 扩大我作为翻译研究人员的技能。我的科学咨询委员会由完成 具有肿瘤学专业知识，肺部疾病，脂质生物化学，成纤维细胞生物学和成纤维生物学专业知识的科学家和临床医生 分子生物学。本K01提案中概述的计划将使我成为一个独立的科学 通过严格的职业发展活动来量身定制的，适合我的特定研究目标。