Abstract
Purpose: :
Immunogenic syngeneic tumors can abrogate immune privilege and undergo immune rejection in the eye. In this study, we examined the role of interferon-γ (IFN-γ) and IL-17 in the immune rejection of syngeneic intraocular tumors in mice.
Methods: :
Ad5E1 tumor cells that undergo immune rejection in the eyes of syngeneic C57BL/6 mice were injected into the anterior chamber (AC) of wild-type, anti-IFN-γ treated, and IFN-γ-/- mice and tumor growth was scored. Wild-type mice and IFN-γ-/- mice were depleted of either CD4+ or CD8+ T cells by in vivo administration of monoclonal antibodies. Tumor cells were also transplanted subcutaneously (SC) and tumor growth was scored. IL-17 production was assessed by ELISA analysis of supernatants from CD4+ T cell cultures that had been stimulated with antigen presenting cells pulsed with tumor antigens.
Results: :
Tumors underwent rejection in the eyes of 15/15 wild-type C57BL/6 mice, but grew progressively in the eyes of all 20 IFN-γ-/- mice and in 10/10 T cell-deficient SCID mice. However, Ad5E1 tumors transplanted SC in IFN-γ-/- mice were rejected (N = 22/25). By contrast, tumors transplanted into the eyes of IFN-γ-/- mice grew progressively even in hosts that had previously rejected SC tumors. IFN-γ-independent mechanisms that mediated rejection of SC tumors were ineffectual in the eye. Depletion of either CD4+ or CD8+ T cells prevented the rejection of SC tumors in IFN-γ-/- mice. CD4+ T cells from IFN-γ-/- mice that had rejected SC tumors produced IL-17 when cultured with antigen presenting cells pulsed with tumor antigens. Moreover, treatment with anti-IL-17 antibody prevented rejection of SC tumors in IFN-γ-/- mice.
Conclusions: :
IFN-γ-independent tumor rejection is inhibited in the eye but not at extraocular sites. Rejection of SC tumors in IFN-γ-/- mice requires IL-17, which is produced by tumor-specific CD4+ T cells. The previously reported deficiency IL-6 within the eye may explain the absence of IL-17-dependent rejection of intraocular tumors in IFN-γ-/- mice, as IL-6 is necessary for the generation of Th17 cells in situ. This supports the notion that IL-17-dependent tumor immunity is inhibited in the eye.
Keywords: immune tolerance/privilege • anterior chamber • tumors