Abstract
BackgroundInterferon (IFN)-γ-mediated immune response plays an important role in tumor immunosurveillance. However, the regulation of IFN-γ-mediated tumorigenesis and immune response remains elusive. USP18, an interferon stimulating response element, regulates IFN-α-mediated signaling in anti-viral immune response, but its role in IFN-γ-mediated tumorigenesis and anti-tumor immune response is unknown.MethodIn this study, USP18 in tumorigenesis and anti-tumor immune response was comprehensively appraised in vivo by overexpression or downregulation its expression in murine B16 melanoma tumor model in immunocompetent and immunodeficient mice.ResultsEctopic expression or downregulation of USP18 in B16 melanoma tumor cells inhibited or promoted tumorigenesis, respectively, in immunocompetent mice. USP18 expression in B16 melanoma tumor cells regulated IFN-γ-mediated immunoediting, including upregulating MHC class-I expression, reducing tumor cell-mediated inhibition of T cell proliferation and activation, and suppressing PD-1 expression in CD4+ and CD8+ T cells in tumor-bearing mice. USP18 expression in B16 melanoma tumor cells also enhanced CTL activity during adoptive immunotherapy by prolonging the persistence and enhancing the activity of adoptively transferred CTLs and by reducing CTL exhaustion in the tumor microenvironment. Mechanistic studies demonstrated that USP18 suppressed tumor cell-mediated immune inhibition by activating T cells, inhibiting T-cell exhaustion, and reducing dendritic cell tolerance, thus sensitizing tumor cells to immunosurveillance and immunotherapy.ConclusionThese findings suggest that stimulating USP18 is a feasible approach to induce B16 melanoma specific immune response.
Highlights
The immune system has developed specific mechanisms to induce tumor immunosurveillance and antitumor immune responses [1,2,3]
Mechanistic studies demonstrated that ubiquitin-specific protease 18 (USP18) suppressed tumor cell-mediated immune inhibition by activating T cells, inhibiting T-cell exhaustion, and reducing dendritic cell tolerance, sensitizing tumor cells to immunosurveillance and immunotherapy
These findings suggest that stimulating USP18 is a feasible approach to induce B16 melanoma specific immune response
Summary
The immune system has developed specific mechanisms to induce tumor immunosurveillance and antitumor immune responses [1,2,3]. These include activation of innate immune cells, such as NK cells and phagocytes, and the tumor antigen-specific adaptive immune response. Activated NK cells and CTLs secrete various effector molecules to lyse tumor cells They both secrete the type-II interferon, IFN-γ, to enhance anti-tumor activity, which includes enhancing antigen presentation and promoting the proliferation, expansion and survival of CD8+ T cells [5,6]. USP18, an interferon stimulating response element, regulates IFN-α-mediated signaling in anti-viral immune response, but its role in IFN-γ-mediated tumorigenesis and anti-tumor immune response is unknown
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