Interferon-gamma is required for protecting against intraocular tumor growth after peripheral immunization but not for the generation of tumor-specific cytotoxic T-lymphocytes.

Abstract

Purpose: To determine the effect of interferon-gamma loss on ocular tumor growth after peripheral immunization.

Methods: C57BL/6 or interferon-gamma knock-out mice (IFN-γ KO) were immunized with the syngeneic Ad5E1 tumor (adenovirus type 5 transformed mouse embryo cells) in the anterior chamber (AC), subcutaneously (SC), or in a protective model of SC immunization prior to an AC challenge. Ocular tumor growth was measured by percent AC occupied with tumor. Spleens were isolated from mice and tested for tumor-specific cytotoxic T-lymphocytes (CTLs) using a ⁵¹Cr release assay.

Results: AC immunization of tumor cells into C57BL/6 mice resulted in ocular tumor growth followed by necrotizing immune rejection of the tumor. However, when the same AC immunization was performed in IFN-γ KO mice, the tumor grew progressively in the eyes of all of the mice. SC immunization with the same tumor cells into both C57BL/6 and IFN-γ KO mice resulted in peripheral tumor rejection. Furthermore, both C57BL/6 and IFN-γ KO mice generated tumor- specific CTLs post SC immunization. In a protective immunization model, mice were immunized peripherally with tumor cells prior to an AC challenge. This SC immunization provided protection against ocular tumor growth in 79% of wild-type C57BL/6 mice (N=15/19). Conversely, 100% of the IFN-γ KO mice (N=18/18) developed progressive ocular tumors. Interestingly, both the C57BL/6 and IFN-γ KO mice still generated tumor-specific lysis CTL responses in the periphery, yet only the wild-type C57BL/6 mice rejected their intraocular tumors.

Conclusions: IFN-γ is critical for immune rejection in this intraocular tumor model but is not required for the peripheral rejection of these tumors. Despite the generation of peripheral tumor-specific CTL responses in both C57BL/6 and IFN-γ KO mice, only an IFN-γ replete environment produces a protective immune response within the eye after a peripheral immunization. This suggests that IFN-γ is required for the protective CTLs to either enter or function within the eye.