The Wdr5-H3K4me3 epigenetic axis regulates pancreatic tumor immunogenicity and immune suppression

The WDR5/MLL1-H3K4me3 epigenetic axis is often activated in both tumor cells and tumor-infiltrating immune cells to drive various cellular response in the tumor microenvironment and extensively studied in hematopoietic cancer, but its respective functions in tumor cells and immune cells in the context of tumor growth regulation of solid tumor is still incompletely understood. We report here that WDR5 exhibits higher expression level in human pancreatic tumor tissues compared with normal pancreas. Moreover, WDR5 expression is negatively correlated with patients’ response to chemotherapy or immunotherapy in human colon cancer and melanoma. However, WDR5 expression is positively correlated with HLA level in human cancer cells and H3K4me3 enrichment is observed at the promoter region of the HLA-A, HLA-B, and HLA-C genes in pancreatic cancer cells. Using mouse tumor cell lines and in vivo tumor models, we determined that WDR5 deficiency or inhibition represses MHC I expression in vitro and in vivo in pancreatic tumor cells. Mechanistically, we determine that WDR5 deficiency inhibits H3K4me3 deposition at the MHC I (H2K1) promoter region to repress MHC I (H2Kb) transcription. On the other hand, WDR5 depletion leads to downregulation of immune checkpoints and immunosuppressive cytokines, including TGFb and IL6, in the pancreatic tumor microenvironments. Our data determine that WDR5 not only regulates tumor cell immunogenicity to suppress tumor growth but also activate immune suppressive pathways to promote tumor immune evasion. Selective activation of the WDR5-MHC I pathway and/or selective inhibition of the WDR5-immune checkpoint and WDR5-cytokine pathways should be considered in WDR5-based epigenetic cancer immunotherapy.