T Cell Intrinsic USP15 Deficiency Promotes Excessive IFN-? Production and an Immunosuppressive Tumor Microenvironment in MCA-Induced Fibrosarcoma.

ABSTRACT: USP15 is a deubiquitinase that negatively regulates activation of naive CD4(+) T cells and generation of IFN-?-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-? 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-? production and tumor development. These findings suggest that T cell intrinsic USP15 deficiency causes excessive production of IFN-?, which promotes an immunosuppressive tumor microenvironment during MCA-induced primary tumorigenesis.

SUBMITTER: Zou Q 

PROVIDER: S-EPMC4691552 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature