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 胰腺腺癌（PDAC）是美国癌症相关死亡的第三主要原因 并且仍然是最致命的癌症之一，预计5年生存率<10％。环境的 暴露于化学物质，例如香烟烟雾中发现的化学物质，特工橙（二恶英； TCDD）和饮食 通过未知机制，退伍军人的PDAC事件的持续增长是基础。有力的证据 暗示慢性炎症是暴露于毒素与PDAC肿瘤发生之间的联系 确切的调解人仍然未知。白介素22（IL22）已成为宿主防御中的重要细胞因子 胰腺中的组织修复。尽管通常受到保护，但长期升高的水平一直是 在发育不良和癌症发展方面实施。 IL22产生细胞的定义特征是退休 在毒素结合，芳基烃受体（AHR）上，被认为是代表的“环境传感器” 免疫系统，最近在增加的胰腺IL22信号传导中实施。我们最近发现 AHR配体促进IL22的产生，它可以引起胰腺上皮的早期恶性转化 通过增强ERK信号定位IL22作为毒素介导的可能丢失的链接的细胞 致癌作用。重要问题仍未得到答复，包括IL22中的关键免疫成分 生理和病理状态的分泌。同样未知的是细胞因子信号传导的靶标 成纤维细胞和上皮细胞中活性的报道。关于持续的肿瘤的责任知之甚少 IL22持久性和生长的信号传导，这是具有重要治疗意义的因素。在这项研究中 提案，我们将使用记者小鼠识别正常和取消的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。我们还将调查原则 胰腺中IL22信号的靶标，因为这可以为AHR/IL22轴提供更多的见解。 肿瘤发育。最后，我们将确定AHR封锁是否可以用作临床上有用的方法 破坏毒素介导的肿瘤发生。成功完成此提案将发现一个重要链接 在环境暴露，感染和癌症形成之间，并通过 该组织与微环境中的毒素接口。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中的因果剂 将PDAC以及其他与暴露有关的恶性肿瘤转换给退伍军人。