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

作者：Julia R. Krug, Gabriele Rodrian, Katja Petter, Hai Yang, Svetlana Khoziainova, Wei Guo, Alan Bénard, Susanne Merkel, Susan Gellert, Simone Maschauer, Monika Spermann, Maximilian J. Waldner, Peter J. Bailey, Christian Pilarsky, Andrea L. Liebl, Philipp Tripal, Jan Christoph, Elisabeth Naschberger, Roland S. Croner, Vera Schellerer, Christoph Becker, Arndt Hartmann, Thomas Tüting, Olaf Prante, Robert Grützmann, Sergei I. Grivennikov, Michael Stürzl, Nathalie Britzen‐Laurent · 发表于：Gastroenterology · 年份：2022 · DOI：10.1053/j.gastro.2022.11.018 · 被引用次数：69 · 研究领域：Glycosylation and Glycoproteins Research、Ubiquitin and proteasome pathways、Galectins and Cancer Biology

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...