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

Overview

Journal Gastroenterology

Specialty Gastroenterology

Date 2022 Nov 19

PMID 36402190

Authors

Julia Krug

Gabriele Rodrian

Katja Petter

Hai Yang

Svetlana Khoziainova

Wei Guo

Alan Benard

Susanne Merkel

Susan Gellert

Simone Maschauer

Monika Spermann

Maximilian Waldner

Peter Bailey

Christian Pilarsky

Andrea Liebl

Philipp Tripal

Jan Christoph

Elisabeth Naschberger

Roland Croner

Vera S Schellerer

Christoph Becker

Arndt Hartmann

Thomas Tuting

Olaf Prante

Robert Grutzmann

Sergei I Grivennikov

Michael Sturzl

Nathalie Britzen-Laurent

Affiliations

Soon will be listed here.

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.

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References

Pfizenmaier K, Bartsch H, Scheurich P, Seliger B, Ucer U, Vehmeyer K . Differential gamma-interferon response of human colon carcinoma cells: inhibition of proliferation and modulation of immunogenicity as independent effects of gamma-interferon on tumor cell growth. Cancer Res. 1985; 45(8):3503-9. View

Dunn G, Koebel C, Schreiber R . Interferons, immunity and cancer immunoediting. Nat Rev Immunol. 2006; 6(11):836-48. DOI: 10.1038/nri1961. View

Fridman W, Pages F, Sautes-Fridman C, Galon J . The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012; 12(4):298-306. DOI: 10.1038/nrc3245. View

Li C, Lim S, Xia W, Lee H, Chan L, Kuo C . Glycosylation and stabilization of programmed death ligand-1 suppresses T-cell activity. Nat Commun. 2016; 7:12632. PMC: 5013604. DOI: 10.1038/ncomms12632. View

Gabius H, van de Wouwer M, Andre S, Villalobo A . Down-regulation of the epidermal growth factor receptor by altering N-glycosylation: emerging role of β1,4-galactosyltransferases. Anticancer Res. 2012; 32(5):1565-72. View

Balog C, Stavenhagen K, Fung W, Koeleman C, McDonnell L, Verhoeven A . N-glycosylation of colorectal cancer tissues: a liquid chromatography and mass spectrometry-based investigation. Mol Cell Proteomics. 2012; 11(9):571-85. PMC: 3434767. DOI: 10.1074/mcp.M111.011601. View

Fischer T, Thoma B, Scheurich P, Pfizenmaier K . Glycosylation of the human interferon-gamma receptor. N-linked carbohydrates contribute to structural heterogeneity and are required for ligand binding. J Biol Chem. 1990; 265(3):1710-7. View

Schreiber R, Old L, Smyth M . Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science. 2011; 331(6024):1565-70. DOI: 10.1126/science.1203486. View

Stanley P, Sundaram S, Tang J, Shi S . Molecular analysis of three gain-of-function CHO mutants that add the bisecting GlcNAc to N-glycans. Glycobiology. 2004; 15(1):43-53. DOI: 10.1093/glycob/cwh136. View

10.

Londino J, Gulick D, Lear T, Suber T, Weathington N, Masa L . Post-translational modification of the interferon-gamma receptor alters its stability and signaling. Biochem J. 2017; 474(20):3543-3557. PMC: 5967388. DOI: 10.1042/BCJ20170548. View

11.

Skrenta H, Yang Y, Pestka S, Fathman C . Ligand-independent down-regulation of IFN-gamma receptor 1 following TCR engagement. J Immunol. 2000; 164(7):3506-11. DOI: 10.4049/jimmunol.164.7.3506. View

12.

Naschberger E, Croner R, Merkel S, Dimmler A, Tripal P, Amann K . Angiostatic immune reaction in colorectal carcinoma: Impact on survival and perspectives for antiangiogenic therapy. Int J Cancer. 2008; 123(9):2120-9. DOI: 10.1002/ijc.23764. View

13.

Blouin C, Lamaze C . Interferon gamma receptor: the beginning of the journey. Front Immunol. 2013; 4:267. PMC: 3760442. DOI: 10.3389/fimmu.2013.00267. View

14.

Turner P, Houghton J, Petak I, Tillman D, Douglas L, Schwartzberg L . Interferon-gamma pharmacokinetics and pharmacodynamics in patients with colorectal cancer. Cancer Chemother Pharmacol. 2003; 53(3):253-60. DOI: 10.1007/s00280-003-0723-8. View

15.

Mlecnik B, Bindea G, Kirilovsky A, Angell H, Obenauf A, Tosolini M . The tumor microenvironment and Immunoscore are critical determinants of dissemination to distant metastasis. Sci Transl Med. 2016; 8(327):327ra26. DOI: 10.1126/scitranslmed.aad6352. View

16.

Partridge E, Le Roy C, Di Guglielmo G, Pawling J, Cheung P, Granovsky M . Regulation of cytokine receptors by Golgi N-glycan processing and endocytosis. Science. 2004; 306(5693):120-4. DOI: 10.1126/science.1102109. View

17.

Mandal R, Samstein R, Lee K, Havel J, Wang H, Krishna C . Genetic diversity of tumors with mismatch repair deficiency influences anti-PD-1 immunotherapy response. Science. 2019; 364(6439):485-491. PMC: 6685207. DOI: 10.1126/science.aau0447. View

18.

Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C . Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006; 313(5795):1960-4. DOI: 10.1126/science.1129139. View

19.

Sveen A, Johannessen B, Tengs T, Danielsen S, Eilertsen I, Lind G . Multilevel genomics of colorectal cancers with microsatellite instability-clinical impact of JAK1 mutations and consensus molecular subtype 1. Genome Med. 2017; 9(1):46. PMC: 5442873. DOI: 10.1186/s13073-017-0434-0. View

20.

Gebert J, Kloor M, Lee J, Lohr M, Andre S, Wagner R . Colonic carcinogenesis along different genetic routes: glycophenotyping of tumor cases separated by microsatellite instability/stability. Histochem Cell Biol. 2012; 138(2):339-50. DOI: 10.1007/s00418-012-0957-9. View