ABSTRACT - Immune Regulation of Gastric Cancer Gastric cancer is the 4th leading cause of cancer deaths worldwide. Over 90% of gastric cancers are associated with long-term Helicobacter pylori infection. However, the infection alone has limited pathogenic effects on the gastric mucosa. Rather, the infection triggers massive gastric inflammation, which becomes increasingly hyper- active, damaging the stomach and creating the requisite environment for carcinogenesis. However, the mecha- nisms and pathways that regulate the onset of hyperactive inflammation are unknown. Glucocorticoids are potent anti-inflammatory steroid hormones produced by the adrenal glands. We have shown that glucocorticoids are critical for suppressing pathogenic gastric inflammation. Adrenalectomized mice spontaneously develop massive gastric inflammation driving a potentially pre-neoplastic condition called Spasmolytic polypeptide-expressing metaplasia (SPEM). Glucocorticoid signaling is also disrupted in gastric cancers, but the role of these hormones in gastric cancer development and progression has not been studied. The overall goal of this proposal is to establish the role of glucocorticoids in preventing Helicobacter-induced gastric cancer development. Our prelim- inary data suggest that endogenous glucocorticoids are critical regulators of the gastric inflammatory response to Helicobacter infection. Loss of glucocorticoid signaling accelerates gastric epithelial damage, metaplasia, and dysplasia. Thus, the loss of glucocorticoid signaling likely accelerates Helicobacter-induced gastric cancer de- velopment. However, glucocorticoid protection from gastric cancer development has never been studied. Spe- cific Aim 1 will examine how glucocorticoid signaling regulates gastric T cell activation and polarization. Specific Aim 2 will examine how long-term Helicobacter infection disrupts endogenous glucocorticoid signaling within the stomach, promoting hyperactive inflammation even upon Helicobacter eradication. Specific Aim 3 will utilize the INS-GAS mouse model of gastric carcinogenesis to study whether glucocorticoid signaling protects from gastric cancer development. Moreover, we will use fresh tumor samples to examine how glucocorticoid signaling mod- ulates the tumor microenvironment in humans. These studies will be the first to investigate how glucocorticoid signaling regulates gastric cancer development. Ultimately, the knowledge generated here will facilitate the launch of human studies and the development of novel diagnostic and therapeutic strategies to prevent gastric cancer.