N-glycosylation regulates intrinsic IFN-γ resistance in colorectal cancer: implications for immunotherapy

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)

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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.

Item Type:Articles
Keywords:Colon cancer, immune evasion, IFNGR1.
Glasgow Author(s) Enlighten ID:Bailey, Dr Peter
Authors: Krug, J., Rodrian, G., Petter, K., Yang, H., Khoziainova, S., Guo, W., Bénard, A., Merkel, S., Gellert, S., Maschauer, S., Spermann, M., Waldner, M., Bailey, P., Pilarsky, C., Liebl, A., Tripal, P., Christoph, J., Naschberger, E., Croner, R., Schellerer, V. S., Becker, C., Hartmann, A., Tüting, T., Prante, O., Grützmann, R., Grivennikov, S. I., Stürzl, M., and Britzen-Laurent, N.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Gastroenterology
ISSN (Online):1528-0012
Published Online:17 November 2022
Copyright Holders:Copyright © 2022 AGA Institute
First Published:First published in Gastroenterology 164(3): 392-406.e5
Publisher Policy:Reproduced under a Creative Commons License

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