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  • Downregulation of IFN-γR in association with loss of Fas function is linked to tumor progression

    Author(s)
    Yang, Dafeng
    J. Stewart, Trina
    Kimberly, K.
    Georgi, David
    I. Abrams, Scott
    Liu, Kebin
    Griffith University Author(s)
    Stewart, Trina
    Year published
    2008
    Metadata
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    Abstract
    The host immune system functions as an intrinsic surveillance network in the recognition and destruction of tumor cells, and it has been demonstrated that lymphocytes and IFN-g are the primary tumor suppressors of the immune system. However, the immune system can concurrently select for tumor variants with reduced immunogenicity and aggressive phenotypes. We report here that tumor escape variants that have survived CTL adoptive immunotherapy exhibited decreased expression levels of both Fas and IFN-gR in vitro. Furthermore, examination of spontaneously arising mouse primary mammary carcinoma and lung metastases revealed ...
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    The host immune system functions as an intrinsic surveillance network in the recognition and destruction of tumor cells, and it has been demonstrated that lymphocytes and IFN-g are the primary tumor suppressors of the immune system. However, the immune system can concurrently select for tumor variants with reduced immunogenicity and aggressive phenotypes. We report here that tumor escape variants that have survived CTL adoptive immunotherapy exhibited decreased expression levels of both Fas and IFN-gR in vitro. Furthermore, examination of spontaneously arising mouse primary mammary carcinoma and lung metastases revealed that both Fas and IFN-gR protein levels were dramatically lower in lung metastases than in primary tumors in vivo. Functional disruption of either the Fas- or the IFN-g signaling pathway enhanced the colonization efficiency of preexisting metastatic tumor cells, whereas disruption of both Fas and IFN-gR pathways resulted in synergistic augmentation of the colonization efficiency of the preexisting metastatic tumor cells, as determined by experimental lung metastases assay. Gene expression profiling revealed that altered expression of genes involved in immediate IFN-gR signaling, the interferon primary response, apoptosis and tumor colonization is associated with loss of IFN-gR function and enhanced metastatic potential. Interestingly, disruption of IFN-gR function did not alter tumor cell susceptibility to CTL-mediated cytotoxicity, but is linked to enhanced infiltration of endogenous T cells in the tumor microenvironment in vivo. These findings suggest that coordinate downregulation of Fas and IFN-gR, 2 key components of cancer immunosurveillance system on tumor cells, leads to a more aggressive metastatic phenotype.
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    Journal Title
    International Journal of Cancer
    Volume
    122
    Issue
    2
    DOI
    https://doi.org/10.1002/ijc.23090
    Subject
    Cancer Cell Biology
    Oncology and Carcinogenesis
    Publication URI
    http://hdl.handle.net/10072/49745
    Collection
    • Journal articles

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