Bioinformatic-experimental screening uncovers multiple targets for increase of MHC-I expression through activating the interferon response in breast cancer

Expression of major histocompatibility complex I (MHC-I) on tumor cells is extremely important for antitumor immune response for its essential role in activating various immune cells including tumor-specific CD8+ T cells. Cancers of low MHC-I expression are commonly of little immune cell infiltration and exhibit poor prognosis in clinic. In this study, we conducted a bioinformatic-experimental screening to identify potential gene targets to enhance MHC-I expression in breast cancer. Through combination of MHC-I scoring, gene expression correlation analysis, and survival prognostication, we identify 243 genes negatively correlated with MHC-I expression in breast cancer, of which 144 genes were further identified as negative correlation factors for tumor-infiltrated lymphocytes. Finally, we verified partially according to KEGG or gene-dependency analysis in breast cancer MCF7 cells, and figured out multiple genes including PIP5K1A, NCKAP1, CYFIP1, DIS3, TBP and EXOC1 as potent gene targets for increase of MHC-I expression in breast cancer. Mechanistically, knockout each of these genes activates the intrinsic interferon response in breast cancer cells, which not only promoted MHC-I expression but also caused immunogenic death of breast cancer cells. Collectively, we identified multiple gene targets for increase of MHC-I expression in breast cancer.