N-glycosylation Regulates Intrinsic IFN-γ Resistance in Colorectal Cancer: Implications for Immunotherapy

Krug J, Rodrian G, Petter K, Yang H, Khoziainova S, Guo W, Benard 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, Becker C, Hartmann A, Tüting T, Prante O, Grützmann R, Grivennikov SI, Stürzl M, Britzen-Laurent N (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Gastroenterology Elsevier

DOI: 10.1053/j.gastro.2022.11.018

Abstract

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.

Authors with CRIS profile

Julia Krug Professur für Molekulare und Experimentelle Chirurgie Hai Yang Professur für Chirurgische Forschung Alan Benard Department of Surgery Susanne Merkel Department of Surgery Simone Maschauer Department of Nuclear Medicine Monika Spermann Maximilian Waldner Lehrstuhl für Innere Medizin I (Medizin 1) Christian Pilarsky Professur für Chirurgische Forschung Andrea Liebl Professur für Molekulare und Experimentelle Chirurgie Philipp Tripal Department of Surgery Jan Christoph Lehrstuhl für Medizinische Informatik Elisabeth Naschberger Department of Surgery Vera Schellerer Department of Surgery Christoph Becker Professur für Molekulare Gastroenterologie Arndt Hartmann Lehrstuhl für Allgemeine Pathologie und Pathologische Anatomie Olaf Prante Professur für Molekulare Bildgebung und Radiochemie Robert Grützmann Department of Surgery Michael Stürzl Professur für Molekulare und Experimentelle Chirurgie Nathalie Britzen-Laurent Professur für Molekulare und Experimentelle Chirurgie

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung (IZKF)

Related research project(s)

D034: Role of fibroblast polarization in the pathogenesis of colorectal carcinoma May 1, 2020 - July 31, 2023

Involved external institutions

University of Glasgow GB United Kingdom (GB) Universitätsklinikum Magdeburg A.ö.R. DE Germany (DE) Fox Chase Cancer Center US United States (USA) (US)

How to cite

APA:

Krug, J., Rodrian, G., Petter, K., Yang, H., Khoziainova, S., Guo, W.,... Britzen-Laurent, N. (2023). N-glycosylation Regulates Intrinsic IFN-γ Resistance in Colorectal Cancer: Implications for Immunotherapy. Gastroenterology. https://doi.org/10.1053/j.gastro.2022.11.018

MLA:

Krug, Julia, et al. "N-glycosylation Regulates Intrinsic IFN-γ Resistance in Colorectal Cancer: Implications for Immunotherapy." Gastroenterology (2023).

BibTeX: Download