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Tumor suppressor TET2 promotes cancer immunity and immunotherapy efficacy
Yan-ping Xu, … , Jeffrey Aubé, Yue Xiong
Yan-ping Xu, … , Jeffrey Aubé, Yue Xiong
Published July 16, 2019
Citation Information: J Clin Invest. 2019;129(10):4316-4331. https://doi.org/10.1172/JCI129317.
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Research Article Cell biology Oncology

Tumor suppressor TET2 promotes cancer immunity and immunotherapy efficacy

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Abstract

Loss-of-function mutations in genes encoding TET DNA dioxygenase occur frequently in hematopoietic malignancy, but rarely in solid tumors, which instead commonly have reduced activity. The impact of decreased TET activity in solid tumors is not known. Here we show that TET2 mediates the IFN-γ/JAK/STAT signaling pathway to control chemokine and PD-L1 expression, lymphocyte infiltration, and cancer immunity. IFN-γ stimulated STAT1 to bind TET2 and recruit TET2 to hydroxymethylate chemokine and PD-L1 genes. Reduced TET activity was associated with decreased Th1-type chemokines and tumor-infiltrating lymphocytes and the progression of human colon cancer. Deletion of Tet2 in murine melanoma and colon tumor cells reduced chemokine expression and tumor-infiltrating lymphocytes, enabling tumors to evade antitumor immunity and to resist anti–PD-L1 therapy. Conversely, stimulating TET activity by systematic injection of its cofactor ascorbate/vitamin C increased chemokines and tumor-infiltrating lymphocytes, leading to enhanced antitumor immunity and anti–PD-L1 efficacy and extended lifespan of tumor-bearing mice. These results suggest an IFN-γ/JAK/STAT/TET signaling pathway that mediates tumor response to anti–PD-L1/PD-1 therapy and is frequently disrupted in solid tumors. Our findings also suggest TET activity as a biomarker for predicting the efficacy of and patient response to anti–PD-1/PD-L1 therapy, and stimulation of TET activity as an adjuvant immunotherapy of solid tumors.

Authors

Yan-ping Xu, Lei Lv, Ying Liu, Matthew D. Smith, Wen-Cai Li, Xian-ming Tan, Meng Cheng, Zhijun Li, Michael Bovino, Jeffrey Aubé, Yue Xiong

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Figure 5

TET2 mediates the IFN-γ/JAK2/STAT1 signaling pathway to activate Th1-type chemokine and PD-L1 gene expression.

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TET2 mediates the IFN-γ/JAK2/STAT1 signaling pathway to activate Th1-typ...
(A) IFN-γ promoted TET2-STAT1 binding. THP-1 cells were treated with or without IFN-γ, and the interaction of TET2 and STAT1 was determined by IP–Western blot. (B) Y701F mutation disrupted TET2-STAT1 binding. STAT1-WT and Y701 mutant plasmids were transfected into THP-1 cells and treated with IFN-γ, and their binding to TET2 was determined by IP–Western blot. (C and D) IFN-γ promoted TET2 binding to the CXCL10 (C) and PD-L1 (D) promoters. THP-1 cells were treated with or without IFN-γ, and TET2 binding to the CXCL10 (C) and PD-L1 (D) promoters was determined by TET2 ChIP-qPCR. Error bars represent ± SD for triplicate experiments. (E and F) IFN-γ increased the 5hmC level of the CXCL10 (E) and PD-L1 (F) promoters. hMeDIP assays were performed in control and TET2-KO THP-1 cells treated or untreated with IFN-γ. 5hmC levels on the CXCL10 (E) and PD-L1 (F) promoters were determined by qPCR. Error bars represent ± SD for triplicate experiments. (G and H) JAK2 inhibitor blocked binding to (G) and demethylation of (H) the CXCL10 promoter by TET2 upon IFN-γ treatment. THP-1 cells were treated with IFN-γ and JAK2 inhibitor as indicated, and the ability of TET2 to bind to (G) and demethylate (H) the CXCL10 promoter was determined by TET2 (G) or 5hmC (H) ChIP-qPCR. Error bars represent ± SD for triplicate experiments. (I and J) JAK2 inhibitor blocked binding to (I) and demethylation of (J) the PD-L1 promoter by TET2 upon IFN-γ treatment. THP-1 cells were treated with IFN-γ and JAK2 inhibitor as indicated, and the ability of TET2 to bind to (I) and demethylate (J) the PD-L1 promoter was determined by TET2 (I) or 5hmC (J) ChIP-qPCR.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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