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IFN- Can Promote Tumor Evasion of the Immune System In Vivo by Down-Regulating Cellular Levels of an Endogenous Tumor Antigen¹

Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104

Although IFN- has been generally thought to enhance antitumor immune responses, we found that IFN- can promote tumor escape in the CT26 colon carcinoma by down-regulating the protein expression of an endogenous tumor Ag. gp70, the env product of the endogenous ecotropic murine leukemia virus, has been reported to be the immunodominant Ag of CT26. We show that IFN- down-regulates intracellular and surface levels of gp70 protein resulting in a reduced lysis by CTL, which is restored by pulsing IFN--treated CT26 with the L^d-restricted immunodominant AH1 epitope derived from gp70. To investigate the role of CT26 sensitivity to IFN- in vivo, we constructed two variants of CT26, CT26.mugR and CT26.IFN, that are unresponsive to IFN- or express IFN-, respectively. We demonstrate using these variants that tumor responsiveness to IFN- promotes a reduction in tumor immunogenicity in vivo that is correlated with an increased tumor incidence in immune mice. Analysis of the tumors from mice challenged with CT26 or CT26.mugR revealed infiltration of CD8 T cells secreting IFN-. We conclude that IFN- secreted by tumor-infiltrating T cells promotes tumor escape through the down-regulation of the endogenous tumor Ag gp70. These findings have impact on the design of effective antitumor vaccine strategies.

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