RESUMO
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.
Assuntos
Proteínas de Ligação a DNA/imunologia , Imunoterapia , Linfócitos do Interstício Tumoral/imunologia , Melanoma Experimental/imunologia , Melanoma Experimental/terapia , Proteínas Proto-Oncogênicas/imunologia , Proteínas Supressoras de Tumor/imunologia , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Proteínas de Ligação a DNA/genética , Dioxigenases , Humanos , Interferon gama/genética , Interferon gama/imunologia , Linfócitos do Interstício Tumoral/patologia , Melanoma Experimental/genética , Melanoma Experimental/patologia , Camundongos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Proteínas Proto-Oncogênicas/genética , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/imunologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Células THP-1 , Células Th1/imunologia , Células Th1/patologia , Proteínas Supressoras de Tumor/genéticaRESUMO
Phevalin, a cyclic nonribosomal peptide produced by Staphylococcus aureus, has intriguing biological properties. A synthetic route to access phevalin and similar pyrazinone natural products tyrvalin, leuvalin, phileucin, and a few synthetic analogs is described. The reaction sequence involves a one-pot carbamate deprotection/imine formation/aerobic oxidation to form the pyrazinone-containing products.