CD80-CD28 signaling controls the progression of inflammatory colorectal carcinogenesis

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.

Assessment of intratumor immune-microenvironment in colorectal cancers with extranodal extension of nodal metastases

“…This protein is present on dendritic cells, activated B cells and monocytes and its overexpression provides a costimulatory signal necessary for T cell activation and survival. A significant overexpression of CD80 in colonic mucosa has been found in early stages of colorectal carcinogenesis and was demonstrated to play a role in immune surveillance mechanisms in the transition from low-grade to high-grade dysplasia [ 32 , 33 ]. However, a strong CD80 expression has been associated to resistance to adjuvant chemotherapy suggesting the failure of this specific immune surveillance mechanism in advanced stage of digestive tract cancer [ 34 ].…”

Squamous cell carcinoma antigen 1 is associated to poor prognosis in esophageal cancer through immune surveillance impairment and reduced chemosensitivity

“…CD80 is a co‐stimulatory molecule necessary to the proper activation of T cells during antigen presentation . Its expression on epithelial cells was reported to be the main driver of immune surveillance mechanisms in inflammatory colorectal carcinogenesis . Ipilimumab, an anti‐CTLA‐4 Ab (CTLA‐4 is the physiological inhibitor of CD80 and CD86) was indeed declared molecule of the year in 2013 at the beginning of the immunotherapy revolution .…”

“…33 Its expression on epithelial cells was reported to be the main driver of immune surveillance mechanisms in inflammatory colorectal carcinogenesis. 18 Ipilimumab, an anti-CTLA-4 Ab (CTLA-4 is the physiological inhibitor of CD80 and CD86) was indeed declared molecule of the year in 2013 at the beginning of the immunotherapy revolution. 34 The inverse correlation of SCCA1 with CD80 expression on the epithelial cell surface might suggest an important clue on the immune inhibitory role of SCCA1.…”

“…9,[14][15][16][17] Cancer immune surveillance mechanisms might significantly influence the prognosis of EAC, as it does in the case of colorectal cancer. 18 Several studies have indicated that in colorectal cancer the impairment of immune surveillance mechanisms plays a crucial role in cancer recurrence. 19,20 Moreover, peritumoral adipose tissue plays a role in lymph node involvement in EAC.…”

CD80 expression promotes immune surveillance in Barrett’s metaplasia

“…Indeed, we have recently demonstrated that in colonic inflammatory carcinogenesis the progression from dysplasia to invasive cancer is controlled by an effective immune surveillance mechanism mediated by CD80 expression on epithelial cells that can completely clear preneoplastic lesions in a large proportion of cases. 12 Despite improved knowledge about the interactions between immunity and cancer, regulation of the immune system during esophageal carcinogenesis is not yet fully understood. BE and EAC constitute interesting models for chronic inflammation associated with a (pre)malignant disease.…”