Augmenting antitumor immune responses with epigenetic modifying agents

Abstract

Epigenetic silencing of immune-related genes is a striking feature of the cancer genome that occurs in the process of tumorigenesis. This phenomena impacts antigen processing and antigen presentation by tumor cells and facilitates evasion of immunosurveillance. Further modulation of the tumor microenvironment by altered expression of immunosuppressive cytokines impairs antigen-presenting cells and cytolytic T-cell function. The potential reversal of immunosuppression by epigenetic modulation is therefore a promising and versatile therapeutic approach to reinstate endogenous immune recognition and tumor lysis. Pre-clinical studies have identified multiple elements of the immune system that can be modulated by epigenetic mechanisms and result in improved antigen presentation, effector T-cell function, and breakdown of suppressor mechanisms. Recent clinical studies are utilizing epigenetic therapies prior to, or in combination with, immune therapies to improve clinical outcomes.

Keywords: antigen presentation; epigenetics; histone acetylation; methylation; tumor immunotherapy.

Figure 1

Epigenetic modifying agents can enhance multiple aspects of an antitumor immune response. EMAs may boost tumor antigen expression, endogenous antigen processing, increase surface CTA display in context of MHC molecules, and boost presentation to T cells by increasing expression of co-stimulatory molecules. EMAs may also enhance both cellular and cytokine-mediated effector T-cell mechanisms and tumor lysis. EMAs may alter checkpoint inhibition targeting the PD1/PD-L1 and CTLA-4/CD28 axis resulting in more efficient effector T-cell mechanisms.