Interferon-gamma induces PD-L1 expression via IFNGR-JAKSTAT pathway in ovarian cancer
Refereed conference paper presented and published in conference proceedings


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AbstractThe purpose of this study is to investigate underlying mechanism of how cytokine interferon-gamma (IFN-) 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-. Our data showed that IFN- upregulated mRNA and protein expression of PD-L1 signifıcantly in a majority of ovarian cancer cells. The functional IFN- 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- treatment. After knocking down the expression levels of IFNGR1 and IFNGR2 in a ovarian cancer cell line by target gene-specifıc siRNA, our data showed that the IFN--mediated induction of PD-L1 were diminished in the ovarian cancer cells when compared to those with nontargeting
scrambled siRNA controls, indicating the induction of PD-L1 by IFN- is dependent on the presence of IFN- 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--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- 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- treatment. Our data showed that phosphorylated-STAT1 protein and IRF-1 gene expression were up-regulated signifıcantly in a majority of human ovarian cancer cells after IFN- treatment, except IGROV-1 and TOV21G cells. These results suggested that IGROV-1 and TOV21G cells might harbor defects in intracellular JAKSTAT1 signaling. We then examined the presence of JAK1 truncating mutations in human ovarian cancer cell lines by Sanger sequencing, and confırmed 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- signaling in SKOV3 cells. We investigated the IFN--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- induces PD-L1 expression in ovarian cancer cells via IFNGR-JAK-STAT pathway. The failure of IFN--mediated induction of PD-L1 in a minority group of human ovarian cancer cell lines is due to defective IFN- 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).
All Author(s) ListLau Tat-San, Chan Kit-Ying Loucia, Cheung Tak-Hong, Yim So-Fan, Lee Ho-Sze Jacqueline, Kwong Joseph
Name of ConferenceAACR Annual Meeting 2017
Start Date of Conference01/04/2017
End Date of Conference05/04/2017
Place of ConferenceWashington
Country/Region of ConferenceUnited States of America
Proceedings TitleCancer Research
Year2017
Volume Number77
Issue Number13 Supplement
PublisherAACR
Pages164
LanguagesEnglish-United States

Last updated on 2018-20-01 at 18:00