Intraepithelial lymphocytes suppress the intestinal tumor growth by cell-to-cell contact via CD103/E-cadherin signal

Abstract BACKGROUND AIMS The reason why small intestinal cancer is rarer than colorectal cancer is not clear. We hypothesized that intraepithelial lymphocytes (IELs), which are enriched in the small intestine, are the closest immune cells to epithelial cells, exclude tumor cells via cell-to-cell contact. METHODS We developed DPE-GFP x APCmin mice, which is a T cell-reporter mouse with spontaneous intestinal tumors. We visualized the dynamics of IELs in the intestinal tumor microenvironment and the interaction between IELs and epithelial cells and the roles of cell-to-cell contact in anti-intestinal tumor immunity using a novel in vivo live-imaging system and novel in vitro co-culture system. RESULTS In the small intestinal tumor microenvironment, T cell movement was restricted around blood vessels and the frequency of interaction between IELs and epithelial cells was reduced. Genetic deletion of CD103 decreased the frequency of interaction between IELs and epithelial cells and increased the number of small intestinal tumors. In the co-culture system, WT-IELs expanded and infiltrated to intestinal tumor organoids from APCmin mice and reduced the viability of them, which was cell-to-cell contact and the expression of CD103 on IELs dependent. CONCLUSIONS The abundance of IELs in the small intestine may contribute to a low number of tumors, while this system may not work in the colon because of the sparseness of IELs. Strategies to increase the number of IELs in the colon or enhance cell-to-cell contact between IELs and epithelial cells may be effective for the prevention of intestinal tumors in patients with high cancer risk.