KDM5A inhibits anti-tumor immune response through downregulation of antigen presentation pathway in ovarian cancer [RNA-seq]

The infiltration of effector CD8+ T cells into tumors is one of the major predictors of clinical outcome for epithelial ovarian cancer (EOC) patients. Immune cell infiltration is a complex process that could be affected by the epigenetic makeup of the tumor. Here, we demonstrate that a lysine 4 histone H3 (H3K4) demethylase KDM5A impairs immune cell infiltration and inhibits anti-tumor immune response. Mechanistically, KDM5A silences genes involved in antigen processing and presentation pathway. Antigen processing and presentation is a critical step that is required for CD8+ T cells infiltration and activation of CD8+ T cell mediated anti-tumor immune response. KDM5A inhibition restores the expression of antigen presentation pathway in vitro and promotes anti-tumor immune response mediated by CD8+ T cells in vivo in a syngeneic EOC mouse model. Notably, a negative correlation between expression of KDM5A and genes involved in antigen processing and presentation pathway such as HLA-A and HLA-B is observed in the majority of cancer types. In summary, our results establish KDM5A as a regulator of CD8+ T cells tumor infiltration and demonstrate that KDM5A inhibition is a novel therapeutic strategy aiming to boost anti-tumor immune response. Overall design: RNA-seq of KDM5A WT and KO cells.