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 而且仍然是最致命的癌症之一，预计5年生存率为10%。环境 暴露于香烟烟雾、橙剂(二恶英；TCDD)和饮食中的化学物质可能 退伍军人中PDAC发病率的持续上升是通过未知的机制进行的。强有力的证据 暗示慢性炎症是暴露于毒素和PDAC肿瘤发生之间的联系，尽管 具体的调解人仍不清楚。白介素22(IL22)已成为一种重要的宿主防御细胞因子 以及胰腺的组织修复。尽管总体上具有保护性，但长期升高的水平一直是 与异型增生和癌症的发展有关。产生IL22的细胞的一个决定性特征是它们的依赖 在毒素结合上，芳香烃受体(AhR)被认为代表着一种环境传感器 免疫系统，最近参与了胰腺IL-22信号的增加。我们最近发现， AHR配体促进IL-22的产生可诱导胰腺上皮细胞早期恶变 细胞通过增强ERK信号定位IL22可能是毒素介导的缺失环节 致癌。重要的问题仍然没有得到解答，包括IL22中的关键免疫成分 生理和病理状态下的分泌物。同样未知的是细胞因子信号转导的靶标 关于成纤维细胞和上皮细胞活性的报道。对于肿瘤对持续时间的依赖知之甚少 IL22是持续性和生长的信号，这是一个具有重要治疗意义的因素。在这项研究中 提议，我们将使用报告小鼠来确定正常和癌症中IL22的细胞来源 并确定AhR配体在激活这些细胞中的作用。我们还将调查这一原则 胰腺中IL22信号的靶点，因为这可以提供对AhR/IL22轴更深入的了解 肿瘤的发展。最后，我们将确定AhR阻断是否可以作为一种临床上有用的方法 干扰性毒素介导的肿瘤发生。这项提案的成功完成将揭示一个重要的联系 环境暴露、炎症和癌症形成之间的关系，并通过 这些组织与微环境中的毒素相互作用。制定降低某一因素的策略 以前被确定为慢性胰腺炎和癌症形成的致病因素将直接 对患有PDAC和其他暴露相关恶性肿瘤的退伍军人的可译性。

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.