Therapeutic potential of DNA methyltransferase inhibitors with immune checkpoint inhibitor therapy in breast cancer

Abstract

Immune checkpoint inhibitor (ICI) therapy has changed the landscape of cancer treatment, particularly for high-mutation burden cancers. However, ICI therapy has thus far demonstrated limited efficacy in breast cancers, where tumor mutation rates are intermediate. Nonetheless, because of limited but positive signals in early trials, combinations of therapies to enhance anti-tumor immunity, and thus response to ICIs in breast cancer, are actively being sought. Our laboratory recently found that guadecitabine, a next-generation DNA methyltransferase inhibitor (DMTi), potentiated cytotoxic CD8+ T cell responses in breast cancer, which appeared to occur by the following mechanisms: (1) DMTi treatment hypomethylated and up-regulated both baseline and IFN-γ-induced MHC-I expression, thereby enhancing antigen presentation capacity, (2) DMTi treatment increased Cxcr3 ligands/chemokines (i.e., Cxcl9, Cxcl10, and Cxcl11) expression and recruited cytotoxic CD8+ T cells into the tumors and (3) DMTi treatment activated NFκB signaling, presumably through the expression of endogenous retroviral (ERV) sequences in tumor cells, initiating an innate response observed in other solid tumor types [Luo et al., Nat Commun 9(1):248]. Most importantly, DMTi treatment primed breast cancer and improved responses to anti-PD-L1 therapy.

Keywords

• epigenetic
• DNA methyltransferase
• immunotherapy
• PD-L1
• NFkB
• cytotoxic T cells
• MHC