Epigenetic Modulation with Histone Deacetylase Inhibitors in Combination with Immunotherapy

Abstract

Understanding the contribution of dysregulated gene silencing to epigenomic alterations in cancer development provides the rationale for the use of epigenetic modulators, such as histone deacetylase (HDAC) inhibitors, in cancer therapy. HDAC inhibitors have been approved as single agents for cutaneous and peripheral T-cell lymphoma and have shown promising activity in reversing therapy resistance in other tumor types. The effects of HDAC inhibitors on immune modulation have created a recent interest in their potential role in immunotherapy. This review describes the current understanding on integrating HDAC inhibitors into various immunotherapeutic approaches, such as cancer vaccines, adoptive T-cell transfer and immune checkpoint inhibitors. Furthermore, it summarizes promising treatment strategies in epigenetic immune priming from clinical trials that are currently underway.

The urgent need to recover MHC class I in cancers for effective immunotherapy

“…There is accumulating evidence suggesting that the efficacy of traditional (IL2, BCG, peptides, etc.) and newly developed immunotherapy (‘immune checkpoint’ blocking antibodies) depends on the expression levels of MHC-I on tumors cells [49]. ‘Soft’ MHC-I molecular lesions can be recovered by a variety of interventions that modify tumor microenvironment in such a way that Th1 type cytokines are released.…”

“…An attractive strategy for the restoration of MHC-I expression is by epigenetic modifiers, like inhibitors of DNA methyltransferase (DNMT) or histone deacetylase (HDAC). In several recent papers, such regulation at the epigenetic level was shown to be able to synergize with immunotherapy for the eradication of mouse tumor models [48, 49, 50•]. Interestingly, IFN-γ-induced restoration of ‘soft’ lesions of MHC-I, one of the most powerful inducers of this gene, was shown to partly mediate its effect by inducing demethylation of antigen-processing machinery related genes, including the TAP genes and LMP-2 [51].…”

HDACs and HDAC Inhibitors in Cancer Development and Therapy

“…The efficacy of HDACi can be significantly enhanced by the concurrent administration of various immunotherapeutic approaches, such as cancer vaccines, adoptive T-cell transfer and immune checkpoint inhibitors (Park et al 2015). For example, co-administration of HDACi with antibodies against cytotoxic T-lymphocyte antigen 4 (CTLA4) could further enhance the infiltration of CD4+ T cells and achieve a synergistic therapeutic effect on tumors by promoting antitumor immune responses (Cao et al 2015).…”

Epigenetic Modifiers in Immunotherapy: a Focus on Checkpoint Inhibitors

“…Hence, there has been an increased interest in developing T cells as a therapeutic target not only for their ability to mount an immune response to tumor components, but also for their direct ability to eliminate tumor cells [60].…”