Oncotarget 2015-08-21

CD80-CD28 signaling controls the progression of inflammatory colorectal carcinogenesis.

Marco Scarpa, Paola Brun, Melania Scarpa, Susan Morgan, Andrea Porzionato, Andromachi Kotsafti, Marina Bortolami, Andrea Buda, Renata D'Incà, Veronica Macchi, Giacomo C Sturniolo, Massimo Rugge, Romeo Bardini, Ignazio Castagliuolo, Imerio Angriman, Carlo Castoro

Index: Oncotarget 6 , 20058-69, (2015)

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Abstract

In patients with ulcerative colitis (UC) the cumulative risk of colon cancer is lower than the actual rate of dysplasia suggesting an efficient immune surveillance mechanism. Since the co-stimulatory molecule CD80 is overexpressed in dysplastic colonic mucosa of UC patients and T-cell activation entails effective costimulation, we aimed to evaluate the functional implication of CD80 signaling in colonic UC-associated carcinogenesis. In humans, we observed that the percentage of CD80+ and HLA-A+ IEC was increased in the dysplastic colonic mucosa of UC patients. In vitro, IEC activated CD8+ T-cells through a CD80-dependent pathway. Finally, in the AOM/DSS-induced colonic adenocarcinoma model CD80 signaling inhibition significantly increased the frequency and extension of high-grade dysplasia, whereas enhancing CD80 activity with an anti-CTLA4 antibody significantly decreased colonic dysplasia. In conclusion, CD80 signaling between IEC and T-cells represents a key factor controlling the progression from low to high grade dysplasia in inflammatory colonic carcinogenesis.