Epigenetic remodeling via HDAC6 inhibition amplifies anti-tumoral immune responses in myeloid leukemia cells

Abstract

Histone deacetylase 6 (HDAC6) has emerged as a promising therapeutic target in cancer due to its immunomodulatory effects. While its prognostic significance remains debated, we demonstrate that HDAC6 loss significantly impairs myeloid leukemia progression in vivo, despite having no functional impact on leukemia cell proliferation in vitro. Global proteome and secretome profiling of HDAC6-knockout (KO) cells revealed upregulation of several immune-related modulators, including RNase T2, a tumor suppressor known to modulate the tumor microenvironment. Notably, RNase T2 upregulation upon HDAC6 loss was restricted to myeloid but not B-ALL cells. Moreover, pharmacological inhibition of HDAC6 recapitulated this phenotype, leading to RNase T2 upregulation in myeloid leukemia cells. ATAC-seq revealed increased chromatin accessibility of RNase T2 following HDAC6 loss, highlighting a functionally epigenetic regulatory contribution. Further functional assays conducted in an immunocompetent setting both ex vivo and in vivo demonstrated that HDAC6 inhibition sensitized murine myeloid leukemia cells to broad CD8+ T cell activation as evidenced by increased TNF and CD107a expression. Consistently, in a syngeneic model, HDAC6 inhibition restricted growth myeloid leukemia cells. Moreover, an extended drug screening analysis identified Cytarabine and Clofarabine as significantly synergizing with HDAC6 inhibitor (Ricolinostat) in myeloid leukemia cell lines and in patient derived xenograft (PDX) cells, while showing limited synergy in lymphoid leukemia cell lines, PDX or healthy control cells. These findings suggest that HDAC6 represents a promising therapeutic target in myeloid lineage derived leukemia cells by simultaneously enhancing immune activation and increasing chemosensitivity.