Notch-Regulated Dendritic Cells Restrain Inflammation-Associated Colorectal Carcinogenesis

Conventional dendritic cells (cDC) play a central role in T-cell antitumor responses. We studied the significance of Notch-regulated DC immune responses in a mouse model of colitisassociated colorectal cancer in which there is epithelial down-regulation of Notch/Hes1 signaling. This defect phenocopies that caused by GMDS (GDP-mannose 4,6-dehydratase) mutation in human colorectal cancers. We found that, although wild-type immune cells restrained dysplasia progression and decreased the incidence of adenocarcinoma in chimeric mice, the immune system with Notch2 deleted in all blood lineages or in only DCs promoted inflammation-associated transformation. Notch2 signaling deficiency not only impaired cDC terminal differentiation, but also downregulated CCR7 expression, reduced DC migration, and suppressed antigen cross-presentation to CD8(+) T cells. Transfer of Notch-primed DCs restrained inflammationassociated dysplasia progression. Consistent with the mouse data, we observed a correlation between infiltrating cDC1 and Notch2 signaling in human colorectal cancers and found that GMDS-mutant colorectal cancers showed decreased CCR7 expression and suppressed cDC1 signature gene expression. Suppressed cDC1 gene signature expression in human colorectal cancer was associated with a poor prognosis. In summary, our study supports an important role for Notch2 signaling in cDC1-mediated antitumor immunity and indicates that Notch2-controlled DCs restrain inflammation-associated colon cancer development in mice.

Automated summary

The study found that Notch2 signaling plays an important role in cDC1-mediated antitumor immunity by regulating DC terminal differentiation, CCR7 expression, and antigen presentation, leading to inhibition of inflammation-associated colon cancer development. Suppressed cDC1 gene signature expression in human colorectal cancer is associated with poor prognosis.