Journal Article

Tumor suppressor TET2 promotes cancer immunity and immunotherapy efficacy

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

2019

Overview

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 interferon γ (IFNγ)-JAK-STAT signaling pathway to control chemokine and PD-L1 expression, lymphocyte infiltration and cancer immunity. IFNγ 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 (TILs) and the progression of human colon cancer. Deletion of Tet2 in murine melanoma and colon tumor cells reduced chemokine expression and TILs, enabling tumors to evade anti-tumor immunity and to resist anti-PD-L1 therapy. Conversely, stimulating TET activity by systematic injection of its co-factor, ascorbate/vitamin C, increased chemokine and TILs, leading to enhanced anti-tumor immunity and anti-PD-L1 efficacy and extended lifespan of tumor-bearing mice. These results suggest an IFNγ-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 and patient response to anti-PD-1/PD-L1 therapy, and stimulating TET activity as an adjuvant immunotherapy of solid tumors.

• Publisher: American Society for Clinical Investigation
• Subject: Adjuvant chemotherapy / Animals / Antitumor activity / Ascorbic acid / B7-H1 Antigen - genetics / B7-H1 Antigen - immunology / Biomarkers / Biomedical research / Blood cancer / Cancer / Cancer treatment / Chemokines / Clonal deletion / Colon cancer / Colorectal cancer / CRISPR / Deoxyribonucleic acid / Development and progression / Dioxygenase / Dioxygenases / DNA / DNA-Binding Proteins - genetics / DNA-Binding Proteins - immunology / Drug therapy / Enzymes / Gastrointestinal diseases / Gene expression / Genes / Genetic aspects / Genomes / Humans / Immunity / Immunotherapy / Interferon / Interferon-gamma - genetics / Interferon-gamma - immunology / Leukemia / Life span / Lymphocytes / Lymphocytes T / Lymphocytes, Tumor-Infiltrating - immunology / Lymphocytes, Tumor-Infiltrating - pathology / Malignancy / Mammals / Medical research / Melanoma / Melanoma, Experimental - genetics / Melanoma, Experimental - immunology / Melanoma, Experimental - pathology / Melanoma, Experimental - therapy / Metastases / Mice / Mutation / Neoplasm Proteins - genetics / Neoplasm Proteins - immunology / Oxidation / PD-1 protein / PD-L1 protein / Programmed Cell Death 1 Receptor - genetics / Programmed Cell Death 1 Receptor - immunology / Proteins / Proto-Oncogene Proteins - genetics / Proto-Oncogene Proteins - immunology / Signal transduction / Signal Transduction - genetics / Signal Transduction - immunology / Solid tumors / Stat1 protein / STAT1 Transcription Factor - genetics / STAT1 Transcription Factor - immunology / Stem cells / Th1 Cells - immunology / Th1 Cells - pathology / THP-1 Cells / Transcription factors / Tumor cells / Tumor suppressor genes / Tumor Suppressor Proteins - genetics / Tumor Suppressor Proteins - immunology / Tumor-infiltrating lymphocytes / Tumors / Vitamin C