Role of Th1/17 in gastric tumor initiation triggered by CTLA4 dysregulation

描述（申请人提供）：胃癌是一种常见的致死性癌症。胃癌的发展被认为是从胃炎症、化生、不典型增生到胃癌。广泛的研究已经确定幽门螺杆菌（HP）感染是胃癌的危险因素，但HP与胃癌的关系在人群中有所不同，可能反映了遗传和环境因素的复杂相互作用。宿主易感因素可能起重要作用，但人们对其了解较少。独立的遗传学研究已经将人类胃癌与CTLA4位点的多态性联系起来，预测CTLA4表达的减少。由于CTLA4仅在T淋巴细胞中表达，并且已被证明是其他类型癌症的抗肿瘤免疫的原型抑制剂，因此遗传学研究的观察结果提示CTLA4在胃癌发生中的矛盾作用。基于ctla4的调节缺陷可能引发异常的炎症级联反应，导致胃肿瘤的发生。由于缺乏自发发生胃炎症和肿瘤的啮齿动物模型，对胃癌宿主易感因素的研究一直受到阻碍。不同于使用“全有或全无”的“敲除”CTLA4模型，我们创建了CTLA4 shRNA“敲除”（KD）模型来模拟人类CTLA4位点多态性预测的CTLA4表达的细微降低。我们发现CTLA4调节可以独立于幽门螺杆菌感染引起自发性胃粘膜化生。我们假设，T淋巴细胞中CTLA4的表达减少通过Th1和/或Th17效应分化失调自发地引发胃肿瘤发生。我们将使用缺乏Th1或Th17的基因突变动物，通过剖析Th1和Th17在CTLA4调节诱导的胃化生中的作用来验证这一假设。本研究旨在提供新的和深入的知识，了解适应性免疫的主抑制剂如何抑制肿瘤发生的开始，并以确定预防胃癌的策略为长期目标。

DESCRIPTION (provided by applicant): Stomach (gastric) cancer is a common lethal cancer. Development of gastric cancer is thought to proceed from gastric inflammation, metaplasia, dysplasia to carcinoma. Extensive studies have established Helicobacter pylori (HP) infection as a risk factor for gastric cancer, but the association of HP with gastric cancers varies in populations, likely reflecting a complex interaction with genetic and environmental factors. Host susceptibility factors may play an important role but are less well-understood. Independent genetic studies have associated human gastric cancer with polymorphisms of the CTLA4 locus that predict a reduction in CTLA4 expression. Since CTLA4 is exclusively expressed in T lymphocytes and has been demonstrated as a prototypical inhibitor of anti-tumor immunity in other types of cancers, observations from the genetic study suggest a paradoxical role of CTLA4 in gastric carcinogenesis. Defect in CTLA4-based regulation could trigger an aberrant inflammatory cascade that lead to gastric tumorigenesis. The study of the host susceptibility factors in gastric cancer has been hindered by a dearth of rodent models that spontaneously develop gastric inflammation and tumors. Rather than using the "all-or-nothing" "knockout" CTLA4 models that do not reflect natural variations of CTLA4 expressions among individual humans, we have created CTLA4 shRNA "knockdown" (KD) models to mimic the subtle reductions of CTLA4 expression predicted by polymorphisms of human CTLA4 locus. We found that CTLA4 modulation could cause spontaneous gastric mucosal metaplasia independently of Helicobacter infection. We hypothesize that Reduced Expression of a CTLA4 in T Lymphocytes Spontaneously Initiates Gastric Tumorigenesis through Dysregulated Th1 and/or Th17 Effector Differentiation. We will test this hypothesis by dissecting the roles of Th1 and Th17 in gastric metaplasia induced by CTLA4 modulation, using genetic mutant animals deficient in Th1 or Th17. This study aims to provide novel and in-depth knowledge on how a master inhibitor of adaptive immunity suppresses initiation of tumorigenesis, with a long-term goal to identify strategies for gastric cancer prevention.