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 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 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 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.

Prognostic Factors for Advanced Colorectal Neoplasia in Inflammatory Bowel Disease: Systematic Review and Meta-analysis.

BACKGROUND AND AIMS: Patients with inflammatory bowel disease (IBD) have an increased risk of colorectal cancer (CRC). We performed a systematic review and meta-analysis to identify all prognostic factors for advanced colorectal neoplasia (aCRN, high-grade dysplasia, or CRC) in patients with IBD. METHODS: A systematic literature search was conducted according to the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. Risk of bias was assessed using the Quality in Prognostic Studies tool. Random-effects models were created separately for odds and hazard ratios, different study designs, and univariable or multivariable data. The evidence for all prognostic factors was categorized as "weak", "moderate", or "strong", based on estimate of effect sizes, heterogeneity, and risk of bias. RESULTS: A total of 164 studies were included, allowing pooled analysis of 31 potential prognostic factors. In the univariable analysis, the evidence for extensive disease was classified as strong while evidence for low-grade dysplasia, strictures, primary sclerosing cholangitis, post-inflammatory polyps, family history of CRC, and ulcerative colitis versus Crohn's disease was considered moderate. Evidence for any dysplasia, colon segment resection, aneuploidy, male sex, and age was classified as weak. In addition, histologic inflammation was identified as a risk factor in multivariable analysis (weak evidence). The evidence for the protective factors colonoscopic surveillance, 5-Aminosalicylic Acid, thiopurines, and smoking was moderate in univariable analysis. Multivariable analysis provided weak evidence for statin use. CONCLUSIONS: In this systematic review and meta-analysis, we identified 13 risk factors and 5 protective factors for aCRN in IBD patients, based on univariable and/or multivariable pooled analyses. These findings might lay the groundwork for an improved CRC risk stratification-based surveillance in IBD.

Systemic Chemotherapy for Metastatic Colitis-Associated Cancer Has a Worse Outcome Than Sporadic Colorectal Cancer: Matched Case Cohort Analysis.

BACKGROUND: Colitis-associated cancers (CAC) are a catastrophic complication of inflammatory bowel disease; at diagnosis, CAC is frequently at an advanced stage. Although the genomic alterations (GA) in CAC are different from sporadic colorectal cancer (CRC), the same systemic therapies are used. We compared clinically relevant outcomes using standard care systemic chemotherapy of stage IV CAC versus a matched patient control cohort of stage IV CRC patients. PATIENTS AND METHODS: A retrospective matched cohort design was used. Eighteen cases of stage IV CAC (7 ulcerative colitis, 11 Crohn disease) and 18 CRC were identified. GA analysis was available for all patients. Outcome endpoints included response rate and response duration, progression-free survival, and OS. RESULTS: Although the response rates were similar (CAC 35.7% vs. CRC 57.1%, P = .45), the median duration of response for CAC was significantly shorter (1.4 months, vs. CRC 11.8 months, P = .006). There was no difference in dose density of first-line therapy between cohorts, suggesting that shorter response duration was due to more rapid development of chemotherapy resistance. Median OS was significantly shorter for CAC patients (13 vs. 27.6 months, P = .034). As expected, there was a difference in the spectrum of GA between CAC and CRC cohorts. However, GA associated with poor prognosis (eg, B-Raf) were no more frequent in the CAC cohort. CONCLUSION: Clinically meaningful outcomes of duration of response and OS are worse for CAC versus sporadic CRC patients treated with FOLFOX or FOLFIRI as first therapy for metastatic disease.