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

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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.