Combining epigenetic and immune therapy to overcome cancer resistance

Abstract

Cancer undergoes "immune editing" to evade destruction by cells of the host immune system including natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). Current adoptive cellular immune therapies include CAR T cells and dendritic cell vaccines, strategies that have yet to show success for a wide range of tumors. Cancer resistance to immune therapy is driven by extrinsic factors and tumor cell intrinsic factors that contribute to immune evasion. These extrinsic factors include immunosuppressive cell populations such as regulatory T cells (T_regs), tumor-associated macrophages (TAMS), and myeloid-derived suppressor cells (MDSCs). These cells produce and secrete immunosuppressive factors and express inhibitory ligands that interact with receptors on T cells including PD-1 and CTLA-4. Immune checkpoint blockade (ICB) therapies such as anti-PD-1 and anti-CTLA-4 have shown success by increasing immune activation to eradicate cancer, though both primary and acquired resistance remain a problem. Tumor cell intrinsic factors driving primary and acquired resistance to these immune therapies include genetic and epigenetic mechanisms. Epigenetic therapies for cancer including DNA methyltransferase inhibitors (DNMTi), histone deacetylase inhibitors (HDACi), and histone methyltransferase inhibitors (HMTi) can stimulate anti-tumor immunity in both tumor cells and host immune cells. Here we discuss in detail tumor mechanisms of immune evasion and how common epigenetic therapies for cancer may be used to reverse immune evasion. Lastly, we summarize current clinical trials combining epigenetic therapies with immune therapies to reverse cancer immune resistance mechanisms.

Keywords: Cancer; DNA methyltransferase inhibitor; Epigenetic; Histone deacetylase inhibitor; Immune evasion.

Figure 1.. DNMTi and HDACi promote anti-tumor immune signaling.

DNMTi treatment removes methylation from endogenous double-stranded RNA species, including ERVs, which activate Type I and III interferon signaling through sensors including TLR3 and MDA5. This signaling in turn leads to increased expression of antigen processing and presentation machinery including MHC I on the cell surface. DNMTis also upregulate cancer testis antigens (CTAs) and the cytokine CCL5 by demethylation of their promoter regions. HDACi increase antigen processing and presentation and PD-L1 expression, along with DNMTi. DNMTi increase T cell activation against tumor cells and both DNMTi and HDACi repress MDSCs, promoting an anti-tumor immune microenvironment.