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-gamma 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-gammaR in vitro. Furthermore, examination of spontaneously arising mouse primary mammary
carcinoma and lung
metastases revealed that both Fas and
IFN-gammaR protein levels were dramatically lower in lung
metastases than in primary
tumors in vivo. Functional disruption of either the Fas- or the IFN-gamma signaling pathway enhanced the colonization efficiency of preexisting metastatic
tumor cells, whereas disruption of both Fas and
IFN-gammaR 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-gammaR signaling, the
interferon primary response, apoptosis and
tumor colonization is associated with loss of
IFN-gammaR function and enhanced metastatic potential. Interestingly, disruption of
IFN-gammaR 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-gammaR, 2 key components of
cancer immunosurveillance system on
tumor cells, leads to a more aggressive metastatic phenotype.