FOXA1 suppresses cancer immunity independent of DNA binding. FOXA1 suppresses cancer immunity independent of DNA binding

Exclusion of lymphocytes from tumors is a major barrier for effective immuno- and chemo-therapy of cancer. We found that FOXA1 overexpression inversely correlates with expression of antigen processing and presentation and interferon signaling genes in different cancer types. FOXA1 binds to STAT proteins and inhibits expression of antigen presentation and interferon response genes and tumor immunity independent of the forkhead domain - DNA binding function. Increased FOXA1 also correlates with immunotherapy resistance in murine triple negative breast tumor and bladder cancer in patients and chemo-resistance in breast cancer patients. Our results reveal that FOXA1 is a key immune suppressor, suggesting that FOXA1 overexpression may predict tumor resistance to immuno- and chemo-therapies and that depletion of FOXA1 may therapeutically convert cancers from ‘immune-cold’ to ‘immune-hot’ diseases. Overall design: To determine the inhibitory effect of FOXA1 variants on the DNA binding ability of STAT2, cells were expressed of Vetor as control, FOXA1-WT, FOXA1-R261G and FOXA1△αH3, and then the endogenous FOXA1 in LNCaP cells was knocked down by specific siRNA for next STAT2 chromatin immunoprecipitation sequencing (ChIP-seq).