PD-L1 facilitates transcription of anti-apoptotic genes IL-8, Bcl3 and STAT1, resulting in increased proliferation of ovarian cancer cells 2247762

Abstract

Abstract Introduction Blocking cell surface expression of PD-L1 has revolutionized immunotherapies, but only a subset of patients achieves durable responses. Indeed, recent studies have also demonstrated PD-L1 nuclear localization that has been associated with cancer progression, but the specific nuclear functions of PD-L1 are just emerging. Here, we investigated the nuclear function of PD-L1 in ovarian cancer (OC) cells. Methods Using gene suppression/overexpression studies, chromatin immunoprecipitation, and cell proliferation and apoptosis studies, we examined whether nuclear PD-L1 regulates apoptosis and expression of anti-apoptotic genes IL-8, Bcl3 and STAT1 in OC cells. We also analyzed the gene co-expression profiles of PD-L1, IL-8 and Bcl3 in OC and pan-cancer tissues using TCGA database. Results Our results demonstrate that PD-L1 overexpression induces PD-L1 nuclear accumulation and increases proliferation of OC cells. Nuclear PD-L1 is recruited to the promoters of IL-8, Bcl3, and STAT1, resulting in their increased expression. Intriguingly, PD-L1 promotes histone acetylation and recruitment of RNA pol II to IL-8, Bcl3 and STAT1 promoters. Suppression of nuclear PD-L1 decreases IL-8, Bcl3 and STAT1 expression and increases apoptosis in OC cells. In addition, analysis of TCGA database demonstrates a positive correlation between PD-L1, IL-8 and Bcl3 gene expression in OC as well as pan-cancer tissues. Conclusion These findings demonstrate that the immune checkpoint PD-L1 facilitates transcription of anti-apoptotic genes IL-8, Bcl3 and STAT1 by inducing promoter acetylation and RNA pol II recruitment, thus providing a novel function of PD-L1 in cancer cells. The increased expression of IL-8, Bcl3 and STAT1 mediated by nuclear PD-L1 might contribute to the limited effectiveness of cancer immunotherapies that target only the surface expression of PD-L1. Funding Source NIH Grant R16GM149263 Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)