Triple Negative Breast Cancer (TNBC) has the worst prognosis among all breast cancer subtypes. The lack of hormonal receptors
and Her2 expression makes targeting with hormone-based treatments or anti-Her2 antibodies ineffective. Furthermore, TNBCs
exhibit the highest expression of the oncogene MYC which negatively affects immune cell function. Natural Killer (NK) cells target
transformed cells like cancer cells and have demonstrated promising clinical efficacy as treatments for hematological malignancies.
However, NK cells have not yet been as successful in treating solid cancers, like breast cancer. The mechanism behind the lack of
efficacy is not well understood, and therefore studies elucidating the mechanism are critical for improving the efficacy of NK cell
therapies. In this study, we show that MYC-overexpression by itself does not affect the NK cell cytotoxicity of TNBC cell lines,
however, if the NK cell response is initiated through antibody-dependent cellular cytotoxicity (ADCC) then MYC expression inhibits
NK cell-mediated killing. Many TNBC cell lines are resistant to classical NK cell cytotoxicity, which we show can be overcome with
ADCC-inducing antibodies. MYC overexpression has an inhibitory effect in two out of three NK cell donors, when overexpressed in
the presence of ADCC-enabling antibodies. This indicates some degree of heterogeneity in MYC regulation of ADCC-dependent
cytotoxicity. Our results also demonstrate that when MYC is overexpressed in TNBC cell lines, NK cell activating ligands are
downregulated on the tumor cell surface, which could explain the MYC-mediated inhibition of NK cells. This is consistent with other
studies where MYC overexpression downregulates NK cell activating ligands in cancer cell lines and inhibits NK cell killing.
Altogether, we demonstrate a functional role of MYC in the inhibition of ADCC-dependent NK cell cytotoxicity in TNBC. These
findings could explain the inhibitory function of tumor cells on NK cells and provide the rationale for exploring MYC-overexpression
as a biomarker for predicting a response of breast cancer patients to NK cell-based immunotherapies.
