Role of environmental toxins in shaping the tumor immune microenvironment

环境毒素在塑造肿瘤免疫微环境中的作用

• 批准号: 10644980
• 负责人: Timothy Louis Frankel
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10644980
• 关键词: Aryl Hydrocarbon Receptor; Binding; Biological Response Modifiers; Cancer Etiology; Cancerous; Cell Communication; Cells; Cessation of life; Chemicals; Chronic; Clinical; Cytokine Signaling; Data; Development; Diet; Dioxins; Dysplasia; Environmental Exposure; Epithelial Cells; Epithelium; Excision; Exposure to; Fibroblasts; Fibrosis; Food; Gastrointestinal tract structure; Genetically Engineered Mouse; Goals; Growth; Health; Helper-Inducer T-Lymphocyte; Host Defense; Human; Hydrocarbons; Immune; Immune system; Incidence; Inflammation; Interleukin Activation; Lead; Lesion; Ligands; Link; Lymphoid Cell; Maintenance; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mediator; Methods; Mus; Organoids; Pancreas; Pancreatectomy; Pancreatic Adenocarcinoma; Pathologic; Physiological; Pollution; Positioning Attribute; Production; Receptor Activation; Receptor Signaling; Reporter; Reporting; Research Proposals; Risk; Role; Shapes; Signal Transduction; Sorting; Source; Specimen; Testing; Tetrachlorodibenzodioxin; Therapeutic; Tissues; Toxic Environmental Substances; Toxin; Tumor-Derived; United States; Veterans; agent orange; aryl hydrocarbon receptor ligand; carcinogenesis; cellular targeting; chronic pancreatitis; cigarette smoke; cytokine; human model; immune activation; immune cell infiltrate; in vivo; inducible Cre; inhibitor; insight; interleukin-22; metaplastic cell transformation; novel; prevent; receptor; receptor expression; recombinase; sensor; single-cell RNA sequencing; tissue repair; transcription factor; tumor; tumor progression; tumor-immune system interactions; tumorigenesis

ABSTRACT Pancreas adenocarcinoma (PDAC) is the third leading cause of cancer related deaths in the United States and remains among the most lethal cancers with an expected 5-year survival of <10%. Environmental exposures to chemicals such as those found in cigarette smoke, Agent Orange (dioxin; TCDD) and diet may underlie a continued rise in PDAC incidence in veterans through unknown mechanisms. Strong evidence implicates chronic inflammation as the link between exposure to toxins and PDAC tumorigenesis though the exact mediators remain unknown. Interleukin-22 (IL22) has emerged as an important cytokine in host defense and tissue repair in the pancreas. Although generally protective, chronically elevated levels have been implicated in development of dysplasia and cancer. A defining feature of IL22-producing cells is their reliance on the toxin binding, aryl hydrocarbon receptor (AhR), thought to represent an “environmental sensor” of the immune system, and recently implicated in increased pancreatic IL22 signaling. We recently discovered that AhR ligands promote IL22 production which can induce early malignant transformation of pancreatic epithelial cells through enhancement of ERK signaling positioning IL22 as the possible missing link in toxin mediated carcinogenesis. Important questions remain unanswered including the critical immune components in IL22 secretion in physiologic and pathologic states. Also unknown is the target of cytokine signaling with previous reports of activity in both fibroblasts and epithelial cells. Little is known about reliance of tumors on sustained IL22 signaling for persistence and growth, a factor that has important therapeutic implications. In this research proposal, we will use reporter mice to identify the cellular sources of IL22 in both the normal and cancerous pancreas and define the role of AhR ligands in activating these cells. We will also investigate the principle target of IL22 signaling in the pancreas as this could provide greater insights into the AhR/IL22 axis during tumor development. Finally, we will determine if AhR blockade could serve as a clinically useful method of disrupting toxin mediated tumorigenesis. Successful completion of this proposal will uncover an important link between environmental exposures, inflammation and cancer formation and identify a novel mechanism by which tissues interface with toxins in the microenvironment. Development of a strategy to decrease a factor previously identified as a causative agent in chronic pancreatitis and cancer formation will have direct translatability to veterans with PDAC as well as other exposure-related malignancies.

抽象的 胰腺癌 (PDAC) 是美国癌症相关死亡的第三大原因 仍然是最致命的癌症之一，预计 5 年生存率<10%。环境的 接触化学物质，例如香烟烟雾、橙剂（二恶英；TCDD）和饮食中的化学物质，可能会导致 退伍军人中 PDAC 发病率持续上升的原因是未知的机制。有力的证据 表明慢性炎症是接触毒素和 PDAC 肿瘤发生之间的联系 确切的中介者仍然未知。白细胞介素 22 (IL22) 已成为宿主防御中的重要细胞因子 和胰腺组织修复。尽管总体上具有保护作用，但长期升高的水平已 与发育不良和癌症的发展有关。 IL22 产生细胞的一个决定性特征是它们的依赖性 与毒素结合的芳基碳氢化合物受体（AhR），被认为代表了生物体的“环境传感器” 免疫系统，最近与胰腺 IL22 信号传导增加有关。我们最近发现 AhR配体促进IL22的产生，从而诱导胰腺上皮的早期恶性转化 通过增强 ERK 信号传导，细胞将 IL22 定位为毒素介导中可能缺失的环节 致癌作用。重要问题仍未得到解答，包括 IL22 中的关键免疫成分 生理和病理状态下的分泌。同样未知的是先前的细胞因子信号转导的目标 成纤维细胞和上皮细胞活性的报告。关于肿瘤对持续性的依赖，人们知之甚少。 IL22 信号传导促进持久性和生长，这是一个具有重要治疗意义的因素。在这项研究中 根据建议，我们将使用报告小鼠来鉴定正常和癌变细胞中 IL22 的细胞来源 胰腺并定义 AhR 配体在激活这些细胞中的作用。我们也来研究一下原理 胰腺中 IL22 信号传导的目标，因为这可以在过程中提供对 AhR/IL22 轴的更深入了解 肿瘤的发展。最后，我们将确定 AhR 阻断是否可以作为临床上有用的方法 破坏毒素介导的肿瘤发生。成功完成这个提案将揭示一个重要的环节 环境暴露、炎症和癌症形成之间的关系，并通过以下方法确定一种新机制： 哪些组织与微环境中的毒素相互作用。制定减少因素的策略 先前被确定为慢性胰腺炎和癌症形成的病原体将有直接的影响 对于患有 PDAC 以及其他与暴露相关的恶性肿瘤的退伍军人来说是可转化的。