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Programme: LiSyM: Liver Systems Medicine 2
Author: Dominic Helm2
Tumour cells can escape antiproliferative pressure by interferon-β through immunoediting of interferon receptor expression

Abstract (Expand)

Abstract Type I interferons (IFNs) play a central role not only in innate immunity against viral infection, but also in the antitumour response, e.g. through a direct impact on cell proliferation. …act on cell proliferation. Particularly for cancer arising in the context of chronic inflammation, constant exposure to IFNs may constitute a strong selective pressure during tumour evolution. Expansion of neoplastic subclones resistant to the antiproliferative effects of IFNs may contribute to immunoediting of tumours, leading to more aggressive disease. Experimental evidence for this development of IFN-insensitivity has been scarce and its molecular mechanism is unclear. In this study we demonstrate that six weeks exposure of cells to IFN-β in vitro reduces their sensitivity to its antiproliferative effects, and that this phenotype was stable for up to four weeks. Furthermore, we observed substantial differences in cellular sensitivity to growth inhibition by IFN-β in a panel of ten different liver cancer cell lines, most prominently in a pair of highly dedifferentiated cell lines, and least in cells from well-differentiated tumours. In both, long-term IFN selection and in dedifferentiated tumour cell lines, we found IFNAR2 expression to be substantially reduced, suggesting the receptor complex to be a sensitive target amenable to immunoediting. Beyond new insights into possible molecular processes in tumour evolution, these findings might prove valuable for the development of biomarkers allowing to stratify tumours for their sensitivity to IFN treatment in the context of patient tailored therapies.

Authors: Felix Hiebinger, Aiste Kudulyte, Huanting Chi, Sebastian Burbano De Lara, Doroteja Ilic, Barbara Helm, Hendrik Welsch, Viet Loan Dao Thi, Ursula Klingmüller, Marco Binder

Date Published: 1st Dec 2023

Publication Type: Journal

Tumour cells can escape antiproliferative pressure by interferon-β through immunoediting of interferon receptor expression (preprint)

Abstract (Expand)

Type I interferons (IFNs) play a central role not only in innate immunity against viral infection, but also in the antitumour response. Apart from indirect immune-modulatory and anti-angiogenic effects, … they have direct impact on cell proliferation. Particularly for cancer arising in the context of chronic inflammation, constant exposure to IFNs may constitute a strong selective pressure during tumour evolution. Expansion of neoplastic subclones or -populations that developed resistance to the antiproliferative effects of IFNs might constitute an important contribution to immunoediting of the cancer cells leading to more aggressive and metastasising disease. Experimental evidence for this development of IFN-insensitivity has been scarce and its molecular mechanism is unclear. In this study we demonstrate that prolonged (six weeks) exposure of cells to IFN-β in vitro reduces their sensitivity to its antiproliferative effects, and that this phenotype was stable for up to four weeks. Furthermore, we observed substantial differences in cellular sensitivity to growth inhibition by IFN-β in a panel of ten different liver cancer cell lines of varying malignity. IFN-resistance was most prominent in a pair of highly dedifferentiated cell lines, and least in cells from well-differentiated tumours, fostering the hypothesis of IFN-driven immunoediting in advanced cancers. In both settings, long-term IFN selection in vitro as well as in dedifferentiated tumour cell lines, we found IFNAR expression to be substantially reduced, suggesting the receptor complex, in particular IFNAR2, to be a sensitive target amenable to immunoediting. Beyond new insights into possible molecular processes in tumour evolution, these findings might prove valuable for the development of biomarkers allowing to stratify tumours for their sensitivity to IFN treatment in the context of patient tailored therapies.

Authors: Felix Hiebinger, Aiste Kudulyte, Huanting Chi, Sebastian Burbano De Lara, Barbara Helm, Hendrik Welsch, Viet Loan Dao Thi, Ursula Klingmüller, Marco Binder

Date Published: 24th Aug 2023

Publication Type: Journal

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