Notch-Regulated Dendritic Cells Restrain Inflammation-Associated Colorectal Carcinogenesis

Abstract

Conventional dendritic cells (cDCs) play a central role in T-cell anti-tumor responses. We studied the significance of Notch-regulated DC immune responses in a mouse model of colitis-associated colorectal cancer (CRC) 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 CRCs. We found that, although wild-type immune cells restrained dysplasia progression and decreased 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 down-regulated CCR7 expression, reduced DC migration and suppressed antigen cross-presentation to CD8+ T cells. Transfer of Notch-primed DCs restrained inflammation-associated dysplasia progression. Consistent with the mouse data, we observed a correlation between infiltrating cDC1 and Notch2 signaling in human CRCs and found that GMDS mutant CRCs showed decreased CCR7 expression and suppressed cDC1 signature gene expression. Suppressed cDC1 gene signature expression in human CRC was associated with a poor prognosis. In summary, our study supports an important role for Notch2 signaling in cDC1-mediated anti-tumor immunity and indicates that Notch2-controlled DCs restrain inflammation-associated colon cancer development in mice.