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

## TL;DR

This study shows that inhibiting HDAC6 boosts immune responses and improves treatment outcomes in myeloid leukemia cells.

## Contribution

The study reveals that HDAC6 inhibition epigenetically upregulates RNase T2 in myeloid leukemia, enhancing anti-tumor immunity and chemosensitivity.

## Key findings

- HDAC6 inhibition increases chromatin accessibility and upregulates RNase T2 in myeloid leukemia cells.
- HDAC6 inhibition enhances CD8+ T cell activation and restricts myeloid leukemia growth in mice.
- Ricolinostat synergizes with Cytarabine and Clofarabine in myeloid leukemia but not in lymphoid or healthy 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 observed in myeloid leukemia cells but not in lymphoblastic leukemia 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 TNFα and CD107a expression. Consistently, in a syngeneic murine model, HDAC6 inhibition restricted the growth of 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.