Role of environmental toxins in shaping the tumor immune microenvironment

摘要 胰腺癌（PDAC）是美国癌症相关死亡的第三大原因 并且仍然是最致命的癌症之一，预期5年存活率<10%。环境 暴露于香烟烟雾、橙子剂（二恶英; TCDD）和饮食中的化学物质， 通过未知机制导致退伍军人PDAC发病率持续上升。有力证据 暗示慢性炎症是暴露于毒素和PDAC肿瘤发生之间的联系， 确切的介质仍然未知。白细胞介素-22（IL-22）已成为宿主防御中的重要细胞因子 以及胰腺组织的修复虽然一般保护，长期升高的水平已经 与发育异常和癌症的发展有关。产生IL 22的细胞的一个决定性特征是它们依赖于 在毒素结合上，芳烃受体（AhR），被认为代表了一种“环境传感器”， 免疫系统，最近与胰腺IL 22信号传导增加有关。我们最近发现 AhR配体促进IL-22产生可诱导胰腺上皮细胞早期恶性转化 通过增强ERK信号传导，将IL 22定位为毒素介导的细胞中可能缺失的环节， 致癌作用重要的问题仍然没有答案，包括IL 22中的关键免疫组分 生理和病理状态下的分泌。同样未知的是细胞因子信号传导的靶点， 报告了成纤维细胞和上皮细胞中的活性。关于肿瘤对持续的 IL 22信号传导的持久性和增长，一个因素，具有重要的治疗意义。本研究 在这项提议中，我们将使用报告小鼠来鉴定正常和癌细胞中IL 22的细胞来源。 胰腺和定义AhR配体在激活这些细胞中的作用。我们还将研究 胰腺中IL 22信号传导的靶点，因为这可以提供对胰腺中AhR/IL 22轴的更深入了解。 肿瘤发展最后，我们将确定AhR阻断是否可以作为一种临床有用的方法， 破坏毒素介导的肿瘤发生。成功完成这一提案将揭示一个重要环节 环境暴露，炎症和癌症形成之间的联系，并确定一种新的机制， 哪些组织与微环境中的毒素接触。制定减少因素的策略 以前被认为是慢性胰腺炎和癌症形成的致病因素， 对于患有PDAC以及其他与癌症相关的恶性肿瘤的退伍军人的可翻译性。

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.