Abstract
Abstract The presence of an interferon-dominated Th1 immune response in colorectal carcinoma (CRC) has been associated with improved clinical outcome. We have previously identified the guanylate-binding protein 1 (GBP-1), one of the major IFN-γ-induced proteins, as a marker for the Th1 immune response and an independent positive prognostic factor in CRC. We also found that GBP-1 is a necessary mediator of the anti-tumorigenic effects of IFNγ. Interestingly, the expression of GBP-1 in CRC was observed more frequently in the desmoplastic stroma than in the directly adjacent tumor cells, suggesting that CRC tumor cells might become resistant to IFN-γ in the course of tumorigenesis. Indeed, we found that several colorectal carcinoma cell lines failed to express GBP-1 or other interferon-stimulated genes after treatment with IFN-γ, and were resistant to IFN-γ-induced apoptosis or proliferation inhibition. In these cell lines, the loss of IFN-γresponsiveness correlated either with the down-regulation of the IFN-γ receptor alpha chain (IFNγRα) or with the presence of a mis-glycosylated form of IFNγRα, which displayed an aberrant intracellular localization. We further validated these findings at the clinical level by showing that the expression of IFNγRα is decreased in CRC compared to normal tissue. In addition, the down-regulation of IFNγRα expression in CRC correlated with a reduced cancer-related survival together with a higher rate of distant metastasis. In addition, in-vivo colon tumorigenesis models using conditional knock-out mice revealed that the absence of IFNγRα expression by intestinal epithelial cells fosters tumor growth. Altogether, our data suggest that the loss of IFN-γ responsiveness is a common event in CRC and protects tumor cells against the anti-tumorigenic effects of IFN-γ. Citation Format: Nathalie Britzen-Laurent, Julia Straube, Philipp Tripal, Maximilian Waldner, Christoph Becker, Susanne Merkel, Roland S. Croner, Michael Sturzl. Role of the interferon-gamma response pathway in immune escape of colorectal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5007. doi:10.1158/1538-7445.AM2017-5007
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