期刊
CELL REPORTS
卷 12, 期 12, 页码 2072-2085出版社
CELL PRESS
DOI: 10.1016/j.celrep.2015.08.035
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资金
- FFG Austrian Research Promotion Agency [BRIDGE-842388-CBL-AIM]
- FWF Austrian Science Fund [W1101-B18, P23537-B13, P25044-B21, T264-B13, M1636-B23]
- Austrian Cancer Society, Tyrol
- Deutsche Forschungsgemeinschaft [DFG WO1877/1-1]
- Austrian Science Fund (FWF) [M1636, P25044] Funding Source: Austrian Science Fund (FWF)
- Austrian Science Fund (FWF) [P 25044, M 1636] Funding Source: researchfish
Nuclear receptor subfamily 2, group F, member 6 (NR2F6) is an orphan member of the nuclear receptor superfamily. Here, we show that genetic ablation of Nr2f6 significantly improves survival in the murine transgenic TRAMP prostate cancer model. Furthermore, Nr2f6(-/-) mice spontaneously reject implanted tumors and develop host-protective immunological memory against tumor rechallenge. This is paralleled by increased frequencies of both CD4(+) and CD8(+) T cells and higher expression levels of interleukin 2 and interferon gamma at the tumor site. Mechanistically, CD4(+) and CD8(+) T cell-intrinsic NR2F6 acts as a direct repressor of the NFAT/AP-1 complex on both the interleukin 2 and the interferon gamma cytokine promoters, attenuating their transcriptional thresholds. Adoptive transfer of Nr2f6-deficient T cells into tumor-bearing immunocompetent mice is sufficient to delay tumor outgrowth. Altogether, this defines NR2F6 as an intracellular immune checkpoint in effector T cells, governing the amplitude of anti-cancer immunity.
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