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.
Authors
Fanhua Kong, Yan Xiong, Liqing Wang, Rongxiang Han, Hossein Fazelinia, Jennifer Roof, Lynn Spruce, Aaron B. Beeler, Wayne W. Hancock
Figure 2
Inhibition of HDAC8 promotes antitumor immunity in an orthotopic HCC model.
