Notch-regulated dendritic cells restrain inflammation-associated colorectal carcinogenesis

Lei Wang, Shuiliang Yu, Ernest R. Chan, Kai Yuan Chen, Cui Liu, Danian Che, Amad Awadallah, Jay Myers, David Askew, Alex Y. Huang, Ivan Maillard, Dan Huang, Wei Xin, Lan Zhou

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

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 colitis-associated colorectal cancer in which there is epithelial downregulation 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 CD8þ 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 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.

Original languageEnglish (US)
Pages (from-to)348-361
Number of pages14
JournalCancer immunology research
Volume9
Issue number3
DOIs
StatePublished - Mar 1 2021

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

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