دورية أكاديمية
N-glycosylation regulates intrinsic IFN-γ resistance in colorectal cancer: implications for immunotherapy
| العنوان: | N-glycosylation regulates intrinsic IFN-γ resistance in colorectal cancer: implications for immunotherapy |
|---|---|
| المؤلفون: | Krug, Julia, Rodrian, Gabriele, Petter, Katja, Yang, Hai, Khoziainova, Svetlana, Guo, Wei, Bénard, Alan, Merkel, Susanne, Gellert, Susan, Maschauer, Simone, Spermann, Monika, Waldner, Maximilian, Bailey, Peter, Pilarsky, Christian, Liebl, Andrea, Tripal, Philipp, Christoph, Jan, Naschberger, Elisabeth, Croner, Roland, Schellerer, Vera S, Becker, Christoph, Hartmann, Arndt, Tüting, Thomas, Prante, Olaf, Grützmann, Robert, Grivennikov, Sergei I, Stürzl, Michael, Britzen-Laurent, Nathalie |
| بيانات النشر: | Elsevier |
| سنة النشر: | 2023 |
| المجموعة: | University of Glasgow: Enlighten - Publications |
| الوصف: | 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)-γ in CRC immunosurveillance, we investigated whether and how acquired IFN-γ resistance in tumor cells would promote tumor growth, and whether IFN-γ sensitivity could be restored. Methods: Spontaneous and colitis-associated CRC development was induced in mice with a specific IFN-γ pathway inhibition in intestinal epithelial cells. The influence of IFN-γ pathway gene status and expression on survival was assessed in patients with CRC. The mechanisms underlying IFN-γ resistance were investigated in CRC cell lines. Results: The conditional knockout of the IFN-γ receptor in intestinal epithelial cells enhanced spontaneous and colitis-associated colon tumorigenesis in mice, and the loss of IFN-γ receptor α (IFNγRα) expression by tumor cells predicted poor prognosis in patients with CRC. IFNγRα expression was repressed in human CRC cells through changes in N-glycosylation, which decreased protein stability via proteasome-dependent degradation, inhibiting IFNγR-signaling. Downregulation of the bisecting N-acetylglucosaminyltransferase III (MGAT3) expression was associated with IFN-γ resistance in all IFN-γ–resistant cells, and highly correlated with low IFNγRα expression in CRC tissues. Both ectopic and pharmacological reconstitution of MGAT3 expression with all-trans retinoic acid increased bisecting N-glycosylation, as well as IFNγRα protein stability and signaling. Conclusions: Together, our results demonstrated that tumor-associated changes in N-glycosylation destabilize IFNγRα, causing IFN-γ resistance in CRC. IFN-γ 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. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | text |
| اللغة: | English |
| العلاقة: | https://eprints.gla.ac.uk/287065/1/287065.pdfTest; Krug, J. et al. (2023) N-glycosylation regulates intrinsic IFN-γ resistance in colorectal cancer: implications for immunotherapy. Gastroenterology , 164(3), 392-406.e5. (doi:10.1053/j.gastro.2022.11.018 ) (PMID:36402190) |
| الإتاحة: | https://doi.org/10.1053/j.gastro.2022.11.018Test https://eprints.gla.ac.uk/287065Test/ https://eprints.gla.ac.uk/287065/1/287065.pdfTest |
| حقوق: | cc_by_nc_nd_4 |
| رقم الانضمام: | edsbas.9631AA0 |
| قاعدة البيانات: | BASE |
| الوصف غير متاح. |