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USP18 is crucial for IFN-?-mediated inhibition of B16 melanoma tumorigenesis and antitumor immunity.

ABSTRACT:

Background

Interferon (IFN)-?-mediated immune response plays an important role in tumor immunosurveillance. However, the regulation of IFN-?-mediated tumorigenesis and immune response remains elusive. USP18, an interferon stimulating response element, regulates IFN-?-mediated signaling in anti-viral immune response, but its role in IFN-?-mediated tumorigenesis and anti-tumor immune response is unknown.

Method

In 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.

Results

Ectopic 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-?-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.

Conclusion

These findings suggest that stimulating USP18 is a feasible approach to induce B16 melanoma specific immune response.

SUBMITTER: Hong B

PROVIDER: S-EPMC4057584 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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USP18 is crucial for IFN-γ-mediated inhibition of B16 melanoma tumorigenesis and antitumor immunity.

Hong Bangxing B Li Haiyan H Lu Yong Y Zhang Mingjun M Zheng Yuhuan Y Qian Jianfei J Yi Qing Q

Molecular cancer 20140531

<h4>Background</h4>Interferon (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.<h4>Method</h4>In this study, USP18 in tumorigenesis and anti-tumor immune response was ...[more]

PMID: 24884733

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