School of Life Sciences, Tianjin University, Tianjin 300072, China.
Institute of Materia Medica, Peking Union Medical College, Beijing 100050, China.
Int J Mol Sci. 2024 Aug 12;25(16):8773. doi: 10.3390/ijms25168773.
The WDR5/MLL1-H3K4me3 epigenetic axis is often activated in both tumor cells and tumor-infiltrating immune cells to drive various cellular responses in the tumor microenvironment and has been 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 a higher expression level in human pancreatic tumor tissues compared with adjacent 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 the 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 significantly 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 (H2K) promoter region to repress MHC I (H2K) transcription. On the other hand, WDR5 depletion leads to the effective downregulation of immune checkpoints and immunosuppressive cytokines, including TGFβ and IL6, in the pancreatic tumor microenvironments. Our data determine that WDR5 not only regulates tumor cell immunogenicity to suppress tumor growth but also activates 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.
WDR5/MLL1-H3K4me3 表观遗传学轴通常在肿瘤细胞和肿瘤浸润免疫细胞中被激活，以驱动肿瘤微环境中的各种细胞反应，并在血液癌症中得到了广泛研究，但在实体瘤肿瘤生长调控的背景下，其在肿瘤细胞和免疫细胞中的各自功能仍不完全清楚。我们在这里报道，与相邻正常胰腺相比，WDR5 在人胰腺肿瘤组织中表达水平更高。此外，在人结肠癌和黑色素瘤中，WDR5 的表达与患者对化疗或免疫治疗的反应呈负相关。然而，WDR5 的表达与人癌细胞中的 HLA 水平呈正相关，并且在胰腺癌细胞中观察到 HLA-A、HLA-B 和 HLA-C 基因启动子区域的 H3K4me3 富集。使用小鼠肿瘤细胞系和体内肿瘤模型，我们确定 WDR5 缺失或抑制显著抑制体外和体内胰腺肿瘤细胞中的 MHC I 表达。从机制上讲，我们确定 WDR5 缺乏抑制 MHC I（H2K）启动子区域的 H3K4me3 沉积以抑制 MHC I（H2K）转录。另一方面，WDR5 耗竭导致胰腺肿瘤微环境中免疫检查点和免疫抑制细胞因子（包括 TGFβ 和 IL6）的有效下调。我们的数据确定，WDR5 不仅调节肿瘤细胞免疫原性以抑制肿瘤生长，而且还激活免疫抑制途径以促进肿瘤免疫逃逸。在基于 WDR5 的表观遗传癌症免疫治疗中，应考虑选择性激活 WDR5-MHC I 途径和/或选择性抑制 WDR5-免疫检查点和 WDR5-细胞因子途径。
