MAdCAM-1 Targeting Strategy Can Prevent Colitic Cancer Carcinogenesis and Progression Via Suppression of Immune Cell Infiltration and Inflammatory Signals.

Chronic inflammation caused by infiltrating immune cells can promote colitis‐associated dysplasia/colitic cancer in ulcerative colitis (UC) by activating inflammatory cytokine signalling through the IL‐6/p‐STAT3 and TNFα/NF‐κB pathways. Mucosal addressin cell adhesion molecule‐1 (MAdCAM‐1) expressed on high endothelial venules promotes the migration of immune cells from the bloodstream to the gut via interaction with α4β7 integrin expressed on the immune cells. MAdCAM‐1, has therefore drawn interest as a novel therapeutic target for treating active UC. However, the role of MAdCAM‐1‐positive endothelial cells in immune cell infiltration in dysplasia/colitic cancers remains unclear. We evaluated the expression of MAdCAM‐1, CD31 and immune cell markers (CD8, CD68, CD163 and FOXP3) in samples surgically resected from 11 UC patients with dysplasia/colitic cancer and 17 patients with sporadic colorectal cancer (SCRC), using immunohistochemical staining. We used an azoxymethane/dextran sodium sulphate mouse model (AOM/DSS mouse) to evaluate whether dysplasia/colitic cancer could be suppressed with an anti‐MAdCAM‐1 blocking antibody by preventing immune cell infiltration. The number of MAdCAM‐1‐positive vessels and infiltrating CD8+, CD68+ and CD163+ immune cells was significantly higher in dysplasia/colitic cancer than in normal, SCRC and UC mucosa. In AOM/DSS mice, the anti‐MAdCAM‐1 antibody reduced the number, mean diameter, depth of tumours, Ki67 positivity, number of CD8+, CD68+ and CD163+ immune cells and the IL‐6/p‐STAT3 and TNF‐α/NF‐κB signalling. Our results indicate that targeting MAdCAM‐1 is a promising strategy for controlling not only UC severity but also carcinogenesis and tumour progression by regulating inflammation/immune cell infiltration in patients with UC.