RESUMEN
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.
Asunto(s)
Proteínas de Unión al ADN/inmunología , Inmunoterapia , Linfocitos Infiltrantes de Tumor/inmunología , Melanoma Experimental/inmunología , Melanoma Experimental/terapia , Proteínas Proto-Oncogénicas/inmunología , Proteínas Supresoras de Tumor/inmunología , Animales , Antígeno B7-H1/genética , Antígeno B7-H1/inmunología , Proteínas de Unión al ADN/genética , Dioxigenasas , Humanos , Interferón gamma/genética , Interferón gamma/inmunología , Linfocitos Infiltrantes de Tumor/patología , Melanoma Experimental/genética , Melanoma Experimental/patología , Ratones , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/inmunología , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/inmunología , Proteínas Proto-Oncogénicas/genética , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT1/inmunología , Transducción de Señal/genética , Transducción de Señal/inmunología , Células THP-1 , Células TH1/inmunología , Células TH1/patología , Proteínas Supresoras de Tumor/genéticaRESUMEN
In this study, we investigated chemical structure of Lycium barbarum polysaccharides and its modulatory effect on oxidative stress in high-fat mice. The polysaccharides mainly contained xylose and glucose. Little amount of rhamnose, mannose and galactose was observed. The Lycium barbarum polysaccharides had IR bands at 800-1200 cm(-1), 1450-1800 cm(-1), 2500-3000 cm(-1), and 3200-3600 cm(-1), which were distinctive absorptions of polysaccharides. Rats are fed with high-fat diet for 2 months. Results showed that blood and liver antioxidant enzymes activities and GSH level in model mice significantly decreased, and MDA level significantly increased (P<0.01) compared to normal control mice. Administration of Lycium barbarum polysaccharides significantly increased antioxidant enzymes activities and decreased MDA level in mice (P<0.01) compared to model group.