Tumor immunotherapy—the potential of epigenetic drugs to overcome resistance

Abstract

Immune checkpoint inhibitors recently introduced into clinical practice have enriched available treatment options for a number of solid cancers. The efficacy of these treatments may however be impaired by tumor cell-intrinsic factors and tumor cell-extrinsic factors resulting in repressed tumor immunogenicity and host immune response. Accordingly, only a subgroup of patients responds to this treatment. Epigenetic drugs may offer an exciting novel approach to reverse immune suppression and to 'prime' tumors for immunotherapy, as DNA methyltransferase (DNMT) inhibitors, histone deacetylase (HDAC) inhibitors and bromodomain and extra-terminal motif (BET) inhibitors show immunomodulatory properties by affecting both cancer cells directly as well as the tumor microenvironment. Upregulation of tumor associated antigens (TAAs), ligands for natural killer (NK) cell receptors, chemokine expression, altered immune checkpoint molecules, antigen procession and presentation as well as induction of viral mimicry improve recognition of cancer cells. In the tumor microenvironment, suppression of myeloid-derived suppressor cells (MDSCs), modulation of regulatory T cells function and activation of NK cells may improve immunogenic efficacy. In conclusion, current preclinical data supports translation of combinatorial treatment approaches into clinical trials and practice.

The Impact of Nutrition and Environmental Epigenetics on Human Health and Disease

“…Furthermore, these epigenetic drugs have recently offered an exciting novel strategy to reverse immune suppression and restore T-cell-mediated anti-tumor activity. A summary of the underlying key mechanisms of epigenetic drugs that ‘prime’ tumors for immunotherapy is presented in [ 100 ]. In addition, these drugs may act as immunomodulatory agents in the treatment of cutaneous T cell lymphoma, in particular by decreasing the expression and secretion of the immunosuppressive cytokine IL-10 and by increasing the expression of the pro-inflammatory cytokine IFN-γ [ 101 ].…”

HDAC inhibitors overcome immunotherapy resistance in B-cell lymphoma

“…Since MHC class I expression is often reduced by epigenetic mechanisms in cancers, HDAC inhibitors can upregulate MHC class I in various types of cancers (Grunewald et al, 2018). In DLBCL cell lines, HDAC inhibitors (trichostatin A, sodium butyrate, apicidin and entinostat) induce MHC class I expression (Cycon et al, 2013).…”

Ovarian Cancer, Cancer Stem Cells and Current Treatment Strategies: A Potential Role of Magmas in the Current Treatment Methods

“…However, new approaches are introduced to enhance the efficacy of checkpoint inhibitors, such as combination of anti-CTLA-4 and anti-PD-1 [171], or a combination of checkpoint inhibitors with chemotherapy, such as PEGylated liposomal doxorubicin or weekly paclitaxel [172], or combination with epigenetic agents [173], antiangiogenic agents such as bevacizumab in combination with PARP inhibitor niraparib (ANITA) [172,173]. A combination of epigenetic therapy (entinostat) with PD-L1 inhibitor avelumab is currently in progress in recurrent OC patients (NCT02915523) [44,173]. These trials may offer additional information into clinical response in OC patients in response to combination of epigenetic and immunotherapy.…”