IFN-gamma can promote tumor evasion of the immune system in vivo by down-regulating cellular levels of an endogenous tumor antigen

Although IFN-gamma has been generally thought to enhance antitumor immune r esponses, we found that IFN-gamma can promote tumor escape in the CT26 colo n carcinoma by down-regulating the protein expression of an endogenous tumo r Ag.gp70, the env product of the endogenous ecotropic murine leukemia viru s, has been reported to be the immunodominant Ag of CT26, We show that IFN- gamma down-regulates intracellular and surface levels of gp70 protein resul ting in a reduced lysis by CTL, which is restored by pulsing IFN-gamma -tre ated CT26 with the L-d-restricted immunodominant AH1 epitope derived from g p70, To investigate the role of CT26 sensitivity to IFN-gamma in vivo, we c onstructed two variants of CT26, CT26.mugR and CT26.IFN, that are unrespons ive to IFN-gamma or express IFN-gamma, respectively, We demonstrate using t hese variants that tumor responsiveness to IFN-gamma promotes a reduction i n tumor immunogenicity in vivo that is correlated with an increased tumor i ncidence in immune mice, Analysis of the tumors from mice challenged with C T26 or CT26.mugR revealed infiltration of CD8 T cells secreting IFN-gamma, We conclude that IFN-gamma secreted by tumor-infiltrating T cells promotes tumor escape through the down-regulation of the endogenous tumor tig gp70, These findings have impact on the design of effective antitumor vaccine str ategies.