Differential effects of HDAC8 targeting on Foxp3+ Tregs and effector T cells promote antitumor immunity

TL;DR

Targeting HDAC8 weakens regulatory T cells while boosting conventional T cells, enhancing the body's ability to fight tumors.

Contribution

HDAC8 targeting differentially affects Treg and effector T cells, offering a novel immuno-oncology strategy.

Findings

HDAC8 inhibition impairs Treg suppressive function in vitro and in vivo.

HDAC8 knockout increases H3K27 acetylation and promotes IL-2, IL-6, Fas, and FasL expression in T cells.

HDAC8 targeting limits tumor growth by enhancing host T cell responses.

Abstract

HDAC8, an evolutionarily distinct, X-linked, zinc-dependent class I histone/protein deacetylase, is implicated in developmental disorders, parasitic infections, myopathy, and cancers. Our study demonstrates the important role of HDAC8 in immune cells by conditional targeting of HDAC8 in murine T cells and application of selective HDAC8 inhibitors. Using flow cytometry, RNA-seq, and ChIP-seq analyses, we demonstrate that knocking down or inhibiting HDAC8 impaired murine regulatory T cell (Treg) suppressive function in vitro and in vivo, but promoted conventional host T cell responses, thereby limiting syngeneic tumor growth. Mechanistically, HDAC8 knockout downregulated Foxp3 expression, enhanced H3K27 acetylation levels, and promoted IL-2, IL-6, Fas, and FasL expression in both Treg and conventional effector T cells. Thus, our combined genetic and pharmacologic studies establish the central importance of HDAC8 in T cell responses and suggest that selective HDAC8 inhibitors represent a potential therapeutic approach in immuno-oncology.

We show HDAC8 is required for normal Foxp3+ Treg function but limits conventional T cell activation such that HDAC8 targeting leads to increased anti-tumor immunity.

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