TY - JOUR
T1 - CD80-CD28 signaling controls the progression of inflammatory colorectal carcinogenesis
AU - Scarpa, Marco
AU - Brun, Paola
AU - Scarpa, Melania
AU - Morgan, Susan
AU - Porzionato, Andrea
AU - Kotsafti, Andromachi
AU - Bortolami, Marina
AU - Buda, Andrea
AU - D'Incà, Renata
AU - Macchi, Veronica
AU - Sturniolo, Giacomo C.
AU - Rugge, Massimo
AU - Bardini, Romeo
AU - Castagliuolo, Ignazio
AU - Angriman, Imerio
AU - Castoro, Carlo
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - Antigen presenting cells
KW - CD8+ T cells
KW - Colorectal carcinogenesis
KW - Intestinal epithelial cells
KW - Ulcerative colitis
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UR - http://www.scopus.com/inward/citedby.url?scp=84940212738&partnerID=8YFLogxK
M3 - Article
AN - SCOPUS:84940212738
VL - 6
SP - 20058
EP - 20069
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 24
ER -