ABSTRACT
Esophageal cancer is a significant health burden in the United States and worldwide and is the 8th leading cause of cancer-related death. Over 90% of esophageal cancers are squamous cell cancers (ESCC). Despite the development of new therapies, the overall 5-year survival rate remains lower than 20%. Recent clinical trials of immunotherapy approaches in ESCC have shown that blocking PD-1/PD-L1 interactions can reduce tumor burden and increase survival, but this only occurs in a fraction of patients. This emphasizes the need for additional therapeutic options to improve overall response rates, duration of response, and overall survival. Glucocorticoid-induced TNFR-related protein (GITR) stimulation has emerged as a promising immunotherapy target, as its stimulation appears to promote tumor regression. In this study, we evaluated the consequences of GITR agonistic stimulation with the DTA-1 antibody (anti-GITR agonist) on esophageal squamous cell carcinoma (ESCC) progression. Increased expression of GITR was observed in esophageal tumors from ESCC patients in comparison to normal adjacent tissue and in a mouse model of ESCC. 100% of mice treated with 4-NQO/IgG control antibody developed invasive squamous cell carcinoma. Less advanced esophageal tumors were seen in mice treated with 4-NQO/anti-GITR agonist compared to 4-NQO/IgG treatment. 4-NQO/anti-GITR agonist-treated mice demonstrated a significant increase in mucosal CTL/Treg ratios as well as decreased gene expression profiles of pathways related to esophageal squamous cell carcinogenesis. Thus, GITR agonism merits further study as a treatment strategy for ESCC patients.
