Class I histone deacetylase inhibition is a novel mechanism to target regulatory T cells in immunotherapy

Abstract

Regulatory T cells (Tregs) represent a major obstacle of cancer immunotherapy. We reviewed here our discovery that Class I histone deacetylase (HDAC) inhibition can functionally target Tregs and help break the immune tolerance. We also discuss the effects of different classes of HDAC inhibitors on Tregs and the underline mechanisms, which may have a direct impact on designing cancer immunotherapy trials involving HDAC inhibitors.

Figure 1. Modulation of Treg function with class-specific HDAC inhibitors. Class I HDAC inhibitors induce acetylation of STAT3 by inhibiting HDAC3 or HDAC1, downregulate Foxp3 gene expression, and suppress Treg function. Class II HDAC inhibitor treatment induces Foxp3 hyperacetylation by targeting HDAC7 and HDAC 9, which leads to stabilization of Foxp3 protein and enhanced Treg function. SIRT1 (class III specific) inhibitor also induces hyperacetylation and stabilization of Foxp3 protein, and enhances the Treg function. A pan inhibitor may target class I HDACs at a low dose and impair Treg function. At a higher dose, the pan inhibitor may target class II HDAC and show a dominant Treg promoting effect.