| First Author | Krug J | Year | 2023 |
| Journal | Gastroenterology | Volume | 164 |
| Issue | 3 | Pages | 392-406.e5 |
| PubMed ID | 36402190 | Mgi Jnum | J:339044 |
| Mgi Id | MGI:7519255 | Doi | 10.1053/j.gastro.2022.11.018 |
| Citation | Krug J, et al. (2023) N-glycosylation Regulates Intrinsic IFN-gamma Resistance in Colorectal Cancer: Implications for Immunotherapy. Gastroenterology 164(3):392-406.e5 |
| abstractText | BACKGROUND & AIMS: Advanced colorectal carcinoma (CRC) is characterized by a high frequency of primary immune evasion and refractoriness to immunotherapy. Given the importance of interferon (IFN)-gamma in CRC immunosurveillance, we investigated whether and how acquired IFN-gamma resistance in tumor cells would promote tumor growth, and whether IFN-gamma sensitivity could be restored. METHODS: Spontaneous and colitis-associated CRC development was induced in mice with a specific IFN-gamma pathway inhibition in intestinal epithelial cells. The influence of IFN-gamma pathway gene status and expression on survival was assessed in patients with CRC. The mechanisms underlying IFN-gamma resistance were investigated in CRC cell lines. RESULTS: The conditional knockout of the IFN-gamma receptor in intestinal epithelial cells enhanced spontaneous and colitis-associated colon tumorigenesis in mice, and the loss of IFN-gamma receptor alpha (IFNgammaRalpha) expression by tumor cells predicted poor prognosis in patients with CRC. IFNgammaRalpha expression was repressed in human CRC cells through changes in N-glycosylation, which decreased protein stability via proteasome-dependent degradation, inhibiting IFNgammaR-signaling. Downregulation of the bisecting N-acetylglucosaminyltransferase III (MGAT3) expression was associated with IFN-gamma resistance in all IFN-gamma-resistant cells, and highly correlated with low IFNgammaRalpha expression in CRC tissues. Both ectopic and pharmacological reconstitution of MGAT3 expression with all-trans retinoic acid increased bisecting N-glycosylation, as well as IFNgammaRalpha protein stability and signaling. CONCLUSIONS: Together, our results demonstrated that tumor-associated changes in N-glycosylation destabilize IFNgammaRalpha, causing IFN-gamma resistance in CRC. IFN-gamma sensitivity could be reestablished through the increase in MGAT3 expression, notably via all-trans retinoic acid treatment, providing new prospects for the treatment of immune-resistant CRC. |
