Epigenetic changes such as histone modifications and DNA methylation are important tumorigenic mechanisms. In Nature, Zou and colleagues show that trimethylation of histone H3K27 mediated by the histone methyltransferase EZH2 and DNA methylation dependent on the enzyme DNMT1 repress induction of the chemokines CXCL9 and CXCL10 in tumor cells and subsequently interfere with the trafficking of effector T cells to the tumor. In a mouse model of ovarian cancer, combined treatment with inhibitors of EZH2 and DNMT1 slows tumor progression and increases the infiltration of effector T cells into the tumor and tumor expression of CXCL9 and CXCL10, which improves the efficacy of blockade of the costimulatory molecule PD-1 or adoptive T cell therapy. Blockade of the chemokine receptor CXCR3 abrogates the beneficial effect of EZH2 and DNMT1 inhibition on tumor progression. Trimethylation of H3K27 and DNA methylation repress tumor-cell chemokine expression independently. In patients, expression of EZH2 and DNMT1 in ovarian tumors is inversely correlated with the number of tumor-infiltrating CD8+ T cells and patient survival.

Nature (26 October 2015) doi:10.1038/nature15520