Epigenetic Silencing of T_H1-Type Chemokines Promotes Tumor Immune Evasion

Enhancer of zeste homologue 2 (EZH2) and DNA methyltransferase 1 (DNMT1) are often involved in the epigenetic silencing of genes in tumorigenesis; however, their roles in cancer immunotherapy are not understood. Peng and colleagues demonstrated that epigenetic silencing of immune-protective genes in cancer can promote tumor progression and reduce immunotherapy response. Combined inhibition of EZH2 (with DZNep) and DNMT (with 5-AZA-dC) in an ovarian cancer mouse model led to reduced tumor size, increased infiltration of T cells, elevated expression of T_H1-type chemokines, and enhanced efficacy of programmed death ligand 1 (PD-L1) blockade and adoptive T-cell therapy. Knockdown or inhibition of EZH2 resulted in increased tumor cell expression of the T_H1-type chemokine ligands CXCL9 and CXCL10 and augmented CD8⁺ T-cell infiltration in human ovarian cancer cells. Mechanistically, chromatin immunoprecipitation experiments revealed that DZNep treatment and EZH2 knockdown reduced trimethylation of lysine 27 of histone 3 (H3K27me3) on the CXCL9 and CXCL10 gene promoters, resulting in decreased expression. Consistent with this finding, microarray experiments in primary ovarian cancer cells identified 20 genes that exhibited altered expression in response to both EZH2 knockdown and GSK126 treatment, including CXCL9 and CXCL10. Additionally, knockdown of DNMT1 or treatment with 5-AZA-dC enhanced CXCL9 and CXCL10 expression, and bisulfite sequencing indicated that 5-AZA-dC treatment reduced CXCL10 DNA methylation, further suggesting that both H3K27me3 and DNA methylation repress the expression of T_H1-type chemokines in ovarian cancer. In human ovarian cancer tissues, high expression of EZH2 and DNMT1 was associated with reduced overall survival and fewer intratumoral CD8⁺ T cells. These findings provide a mechanism to explain why some tumors are inflamed with T cells while others not. The results indicate that epigenetic silencing of T_H1-type chemokines can promote immune evasion and tumor progression, and suggest that epigenetic reprogramming may improve the efficacy of cancer immunotherapy including checkpoint blockade and T-cell therapy.

Peng D, Kryczek I, Nagarsheth N, Zhao L, Wei S, Wang W, et al. Epigenetic silencing of T_H1-type chemokines shapes tumor immunity and immunotherapy. Nature 2015;527:249–53.

• ©2015 American Association for Cancer Research.