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

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 9

VC stimulates TET activity to enhance tumor-infiltrating lymphocytes and anti–PD-L1 immunotherapy.

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VC stimulates TET activity to enhance tumor-infiltrating lymphocytes and...
(A) VC enhanced anti–PD-L1 immunotherapy. Kaplan-Meier survival curves for mice injected with WT or Tet2-KO B16-OVA cells and treated with anti–PD-L1 antibody and VC (sodium ascorbate) as indicated are shown. 2 × 105 WT or Tet2-KO B16-OVA cells, anti–PD-L1 antibody, and sodium ascorbate were injected s.c., i.p., and i.p., respectively, into C57BL/6 mice at the indicated time points. Kaplan-Meier survival curves for these mice are shown (n = 10 mice for each group). The survival curve of mice injected with WT or Tet2-KO B16-OVA cells with anti–PD-L1 treatment in Figure 1E is also shown by a dashed black or red line for reference. The P value was determined using log-rank (Mantel-Cox) test, comparing every 2 groups, and is shown in the table of the figure. *P < 0.05, ***P < 0.001. (B) VC enhanced tumor-infiltrating lymphocytes with anti–PD-L1 immunotherapy. CD8 immunostaining of Tet2-WT and -KO tumors from A treated with anti–PD-L1 antibody and VC is shown. Scale bar: 200 μm. (C) Quantification of CD8+ and CD3+ T cells from B and Supplemental Figure 7C. Average cell number per HPF is shown, with 5 HPFs calculated for each group. **P < 0.01, ***P < 0.001. Quantification of CD8+ and CD3+ T cells of mice injected with anti–PD-L1 in Figure 2, D and E, is also shown for reference. Error bars represent ± SD.