RT Journal Article
SR Electronic
T1 Notch-regulated Dendritic Cells Restrain Inflammation-associated Colorectal Carcinogenesis
JF Cancer Immunology Research
JO Cancer Immunol Res
FD American Association for Cancer Research
SP canimm.0428.2020
DO 10.1158/2326-6066.CIR-20-0428
A1 Wang, Lei
A1 Yu, Shuiliang
A1 Chan, Ernest Ricky
A1 Chen, Kai-Yuan
A1 Liu, Cui
A1 Che, Danian
A1 Awadallah, Amad
A1 Myers, Jay
A1 Askew, David
A1 Huang, Alex Y
A1 Maillard, Ivan
A1 Huang, Dan
A1 Xin, Wei
A1 Zhou, Lan
YR 2021
UL http://cancerimmunolres.aacrjournals.org/content/early/2021/01/12/2326-6066.CIR-20-0428.abstract
AB 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.