Epigenetic modulation of immunotherapy cofactors to enhance tumor response in lung cancer

Abstract

Immunotherapy with a checkpoint inhibitor has revolutionized the treatment of advanced non-small cell lung cancer. Replacing cytotoxic chemotherapy in some settings, immunotherapy with checkpoint inhibitors enables many patients to live longer with much fewer side effects. Nonetheless, immunotherapy alone only works for about one-fifth of unselected patients and despite the durability of response, treatment will eventually fail. There are several important cofactors within the tumor microenvironment which can contribute to the efficacy of immunotherapy. These include T-cells, chemokines, and antigen presentations. Preliminary research has shown that these cofactors can be altered by epigenetic modulation. Specifically, hypomethylating agents or histone deacetylase inhibitors can lead to changes in the compositions and characteristics within the tumor microenvironment in a way that enhances the efficacy of checkpoint inhibitor. In recent clinical trials of combined immuno-epigenetic therapy, tumor responses were observed among patients who were previously resistant or refractory to immunotherapy. Furthermore, biological correlative studies also confirmed the mechanism of action of these agents, especially among patients who derived benefit. Nonetheless, at present, the efficacy in terms of tumor response seems modest and side effects, though mostly not serious, can result in treatment interruption or interfere with the quality of life.

Keywords

• epigenetic histone deacetylase inhibitor checkpoint inhibitor