T Cell Intrinsic USP15 Deficiency Promotes Excessive IFN-γ Production and an Immunosuppressive Tumor Microenvironment in MCA-Induced Fibrosarcoma.
T Cell Intrinsic USP15 Deficiency Promotes Excessive IFN-γ Production and an Immunosuppressive Tumor Microenvironment in MCA-Induced Fibrosarcoma.
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DOI：
10.1016/j.celrep.2015.11.046
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发表时间：
2015-12-22
期刊：
影响因子：
8.8
通讯作者：
Sun SC
中科院分区：
文献类型：
--
作者：
Zou Q;Jin J;Xiao Y;Zhou X;Hu H;Cheng X;Kazimi N;Ullrich SE;Sun SC
USP15 is a deubiquitinase that negatively regulates activation of naïve CD4+ T cells and generation of IFN-γ-producing T helper 1 (Th1) cells. USP15 deficiency in mice promotes antitumor T cell responses in a transplantable cancer model; however, it has remained unclear how deregulated T cell activation impacts primary tumor development during the prolonged interplay between tumors and the immune system. Here, we find that the USP15-deficient mice are hypersensitive to methylcholantrene (MCA)-induced fibrosarcomas. Excessive IFN-γ production in USP15-deficient mice promotes expression of the immunosuppressive molecule PD-L1 and the chemokine CXCL12, causing accumulation of T-bet+ regulatory T cells and CD11b+Gr-1+ myeloid-derived suppressor cells at tumor site. Mixed bone marrow adoptive transfer studies further reveals a T cell-intrinsic role for USP15 in regulating IFN-γ production and tumor development. These findings suggest that T cell intrinsic USP15 deficiency causes excessive production of IFN-γ, which promotes an immunosuppressive tumor microenvironment, during MCA-induced primary tumorigenesis.
