Cooperative downregulation of IFN[gamma]R and Fas is functionally linked to CTL-mediated immunoselection and tumor promotion (50.3)

Abstract The host immune system functions as an intrinsic surveillance network in the recognition and destruction of tumor cells. But the immune system, at the same time can “edit” tumor cells and select for tumor variants with reduced immunogenicity through immunoselection. We report here that Fas and IFNγR were coordinately downregulated in the tumor escape variants in vitro. Examination of spontaneously arising mouse primary mammary carcinoma and lung metastases revealed that both Fas and IFNγR protein levels were also dramatically lower in lung metastases than in primary tumors in vivo. Functional disruption of either the Fas-mediated apoptosis pathway, the IFNγ signaling pathway, or both pathways together enhanced the metastatic capability of tumor cells. Gene expression profiling revealed that altered expression of genes involved in immediate IFNγR signaling, the interferon primary response, apoptosis, and tumor colonization are associated with tumor escape. Furthermore, disruption of IFNγR 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 and tumor promotion in vivo. These findings suggest that coordinate downregulation of Fas and IFNγR by tumor cells, two key components of cancer immunosurveillance and immunoediting, leads to a more aggressive metastatic phenotype.