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 3

Loss of TET2 impairs Th1-type chemokines and PD-L1 expression.

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Loss of TET2 impairs Th1-type chemokines and PD-L1 expression. (A) Delet...
(A) Deletion of Tet2 in allograft tumors reduced chemokine Cxcl9, Cxcl10, and Pdl1 expression. Total mRNA was extracted from WT or Tet2-KO tumor (n = 10 for each group), and mRNA levels of genes were determined by qPCR. Data represent mean ± SD. *P < 0.05, **P < 0.01 by unpaired Student’s t test. (B and C) Knocking out Tet2 blocked IFN-γ–induced chemokines and Pdl1 gene expression in B16-OVA (B) and THP-1 (C) cells. WT or Tet2-KO cells were treated with IFN-γ for 20 hours, and total RNA was extracted. The relative mRNA levels were determined by qPCR. Error bars represent ± SD for triplicate experiments. (D) Knocking out Tet2 decreased IFN-γ–induced CXCL9 and CXCL10 protein levels in B16-OVA cells. WT or Tet2-KO B16-OVA cells were treated with IFN-γ for 72 hours; then medium was collected and subjected to ELISA analysis. Error bars represent ± SD for triplicate experiments. **P < 0.01, ***P < 0.001 by unpaired Student’s t test. (E) TET2 catalytic activity was required for IFN-γ–induced CXCL10 and PD-L1 expression. TET2-WT and catalytic mutant R1896S were overexpressed in TET2-KO THP-1 cells; then cells were treated with IFN-γ for 20 hours as indicated, and total RNA was extracted. The relative mRNA levels were determined by qPCR. Error bars represent ± SD for triplicate experiments. (F) Deletion of Tet2 impaired T cell attraction by Transwell assay. WT or Tet2-KO B16-OVA cells were treated with IFN-γ for 48 hours, and CM was collected. Triplicate independent experiments were performed for each group. Error bars represent ± SD. Bonferroni-adjusted **P < 0.01, with raw P value derived from unpaired Student’s t test.