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.