CD80-CD28 signaling controls the progression of inflammatory colorectal carcinogenesis

// Marco Scarpa 1, * , Paola Brun 2, * , Melania Scarpa 1 , Susan Morgan 3 , Andrea Porzionato 2 , Andromachi Kotsafti 1 , Marina Bortolami 4 , Andrea Buda 4 , Renata D’Inca 4 , Veronica Macchi 2 , Giacomo C. Sturniolo 4 , Massimo Rugge 5 , Romeo Bardini 4 , Ignazio Castagliuolo 2 , Imerio Angriman 4, § , Carlo Castoro 1, § 1 Oncological Surgery Unit, Veneto Institute of Oncology IOV – IRCCS, Padova 35128, Italy 2 Department of Molecular Medicine, University of Padova, Padova 35128, Italy 3 Department of Histopathology, Sheffield Teaching Hospitals, Sheffield S10 2JF, UK 4 Department of Surgery Oncology and Gastroenterology, University of Padova, Padova 35128, Italy 5 Department of Medicine, University of Padova, Padova 35128, Italy * These authors have contributed equally to this work § These senior authors contributed equally to this work Correspondence to: Marco Scarpa, e-mail: marcoscarpa73@yahoo.it Keywords: ulcerative colitis, colorectal carcinogenesis, antigen presenting cells, CD8+ T cells, intestinal epithelial cells Received: September 18, 2014      Accepted: November 19, 2014      Published: January 19, 2015 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.