Abstract 648: Interferon-gamma induces PD-L1 expression via IFNGR-JAK-STAT pathway in ovarian cancer
Authors: Tat-San Lau, Loucia Kit-Ying Chan, Tak-Hong Cheung, So-Fan Yim, Jacqueline Ho-Sze Lee, Joseph Kwong
Journal: Cancer Research (2017)

Abstract The purpose of this study is to investigate underlying mechanism of how cytokine interferon-gamma (IFN-γ) regulates PD-L1 expression in ovarian cancer cells. We treated a panel of human and mouse ovarian cancer cell lines with recombinant human/mouse IFN-γ. Our data showed that IFN-γ up-regulated mRNA and protein expression of PD-L1 significantly in a majority of ovarian cancer cells. The functional IFN-γ receptor is comprised of two ligand-binding IFNGR1 chains associated with two signal-transducing IFNGR2 chains and associated signaling machinery. Here we found that the mRNA expression levels of IFNGR1 and IFNGR2 were abundant in all human ovarian cancer cell lines being tested, while their expressions were not affected by IFN-γ treatment. After knocking down the expression levels of IFNGR1 and IFNGR2 in a ovarian cancer cell line by target gene-specific siRNA, our data showed that the IFN-γ-mediated induction of PD-L1 were diminished in the ovarian cancer cells when compared to those with non-targeting scrambled siRNA controls, indicating the induction of PD-L1 by IFN-γ is dependent on the presence of IFN-γ receptors in the ovarian cancer cells. Although abundant expression of IFNGR1 and IFNGR2 were found in all human ovarian cancer cell lines being tested, the IFN-γ-mediated induction of PD-L1 was not detected in a few of the human ovarian cancer cell lines (namely IGROV-1, TOV21G and SKOV3). We further investigated the integrity of IFN-γ signaling in the human ovarian cancer cell lines by examining activation of STAT1 protein and induction of IRF-1 gene in human ovarian cancer cell lines after IFN-γ treatment. Our data showed that phosphorylated-STAT1 protein and IRF-1 gene expression were up-regulated significantly in a majority of human ovarian cancer cells after IFN-γ treatment, except IGROV-1 and TOV21G cells. These results suggested that IGROV-1 and TOV21G cells might harbor defects in intracellular JAK-STAT1 signaling. We then examined the presence of JAK1 truncating mutations in human ovarian cancer cell lines by Sanger sequencing, and confirmed that IGROV-1 and TOV21G cells, but not the others, have JAK1 truncating mutations. Since our data showed that SKOV3 cells have wild type JAK1, we further investigated other possible defects in IFN-γ signaling in SKOV3 cells. We investigated the IFN-γ-induced STAT3 protein activation in human ovarian cancer cell lines, and defects were found in Y705 STAT3 phosphorylation in SKOV3 as well as in IGROV-1 and TOV21G cells. To summarize, our results showed that IFN-γ induces PD-L1 expression in ovarian cancer cells via IFNGR-JAK-STAT pathway. The failure of IFN-γ-mediated induction of PD-L1 in a minority group of human ovarian cancer cell lines is due to defective IFN-γ signaling, including JAK1 truncating mutations and impaired STAT3 activation. This work is supported by Hong Kong Research Grants Council General Research Fund (467713 and 14109515). Citation Format: Tat-San Lau, Loucia Kit-Ying Chan, Tak-Hong Cheung, So-Fan Yim, Jacqueline Ho-Sze Lee, Joseph Kwong. Interferon-gamma induces PD-L1 expression via IFNGR-JAK-STAT pathway in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 648. doi:10.1158/1538-7445.AM2017-648