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 6

Loss of TET activity is associated with decreased Th1-type chemokines and infiltrating lymphocytes in human colon cancer.

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Loss of TET activity is associated with decreased Th1-type chemokines an...
(A) Infiltrating lymphocyte numbers including CD3+ T cells, CD8+ cytotoxic T lymphocytes (CTLs), and CD56+ NK cells were decreased along with the loss of 5hmC in adenoma of colon. Two representative pictures show multicolor, fluorescently labeled inflammatory cells in adenomas expressing high 5hmC levels and adenomas with decreased 5hmC expression, separately. Scale bars: 100 μm. (B) Quantification of CD3+ T cells, CD8+ CTLs, and CD56+ NK cells in colon adenomas classified by high and low 5hmC staining. Four cases of adenoma with high 5hmC expression and 8 cases of adenoma with low 5hmC expression were used to count cytotoxic T cells (CD3+ and CD8+) and NK cells (CD56+). For each case, 3 areas highly infiltrated with inflammatory cells were selected. **P < 0.01 by Student’s t test. Data represent mean ± SEM. (C) Intratumoral CXCL9, CXCL10, and CXCL11 levels were correlated with 5hmC levels in colon adenomas. Representative photographs show the expression of CXCL9, CXCL10, and CXCL11 in samples with high 5hmC and in samples with low 5hmC in the same fields, on serial sections in adenoma with low-grade dysplasia, adenoma with high-grade dysplasia, and adenocarcinoma specimens. Scale bars: 50 μm. (D–F) Quantification of CXCL9 (D), CXCL10 (E), and CXCL11 (F) expression classified by high and low 5hmC staining. Five samples representing cases with low 5hmC expression and 5 with high 5hmC expression were selected separately in adenoma with low-grade dysplasia, adenoma with high-grade dysplasia, and adenocarcinoma. For each case, 5 fields were randomly selected to calculate the integrated staining density by i-Solution image analysis software. *P < 0.05, **P < 0.01, ***P < 0.001 by unpaired Student’s t test. Data represent mean ± SEM.