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We show that IL27 induces STAT factor phosphorylation in cancerous cell lines of different tissue origin. IL27 leads to STAT1 phosphorylation and recapitulates an IFN-\u03b3-like response in the microarray analyses, with up-regulation of genes involved in antiviral defense, antigen presentation, and immune suppression. Like IFN-\u03b3, IL27 leads to an up-regulation of TAP2 and MHC-I proteins, which mediate increased tumor immune clearance. However, both cytokines also upregulate proteins such as PD-L1 (CD274) and IDO-1, which are associated with immune escape of cancer. Interestingly, differential expression of these genes was observed within the different cell lines and when comparing IL27 to IFN-\u03b3. In coculture experiments of hepatocellular carcinoma (HCC) cells with peripheral blood mononuclear cells, pre-treatment of the HCC cells with IL27 resulted in lowered IL2 production by anti-CD3\/-CD28 activated T-lymphocytes. Addition of anti-PD-L1 antibody, however, restored IL2 secretion. The levels of other TH1 cytokines were also enhanced or restored upon administration of anti-PD-L1. In addition, we show that the suppression of IL27 signaling by IL6-type cytokine pre-stimulation\u2014mimicking a situation occurring, for example, in IL6-secreting tumors or in tumor inflammation\u2013induced cachexia\u2014can be antagonized by antibodies against IL6-type cytokines or their receptors. Therapeutically, the antitumor effects of IL27 (mediated, e.g., by increased antigen presentation) might thus be increased by combining IL27 with blocking antibodies against PD-L1 or\/and IL6-type cytokines.<\/jats:p><jats:p>Anti-IL6 or anti-PD-L1 influence IL27 signaling effects in HCC cells by preventing IL6 mediated inhibition of IL27 or by mediating an increase in immunogenicity, respectively.<\/jats:p>","DOI":"10.1002\/jlb.ma1217-495r","type":"journal-article","created":{"date-parts":[[2018,7,25]],"date-time":"2018-07-25T00:17:39Z","timestamp":1532477859000},"page":"969-985","source":"Crossref","is-referenced-by-count":17,"title":["The PD-L1- and IL6-mediated dampening of the IL27\/STAT1 anticancer responses are prevented by \u03b1-PD-L1 or \u03b1-IL6 antibodies"],"prefix":"10.1093","volume":"104","author":[{"given":"Catherine","family":"Rolvering","sequence":"first","affiliation":[{"name":"University of Luxembourg, Life Sciences Research Unit\u2014Signal Transduction Laboratory , Belvaux, Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas D","family":"Zimmer","sequence":"additional","affiliation":[{"name":"University of Luxembourg, Life Sciences Research Unit\u2014Signal Transduction Laboratory , Belvaux, Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aur\u00e9lien","family":"Ginolhac","sequence":"additional","affiliation":[{"name":"University of Luxembourg, Life Sciences Research Unit\u2014Bioinformatics Core Facility , Belvaux, Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christiane","family":"Margue","sequence":"additional","affiliation":[{"name":"University of Luxembourg, Life Sciences Research Unit\u2014Signal Transduction Laboratory , Belvaux, Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e9lanie","family":"Kirchmeyer","sequence":"additional","affiliation":[{"name":"University of Luxembourg, Life Sciences Research Unit\u2014Signal Transduction Laboratory , Belvaux, Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florence","family":"Servais","sequence":"additional","affiliation":[{"name":"University of Luxembourg, Life Sciences Research Unit\u2014Signal Transduction Laboratory , Belvaux, Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heike M","family":"Hermanns","sequence":"additional","affiliation":[{"name":"University Hospital W\u00fcrzburg, Division of Hepatology , W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"Hergovits","sequence":"additional","affiliation":[{"name":"University Hospital W\u00fcrzburg, Division of Hepatology , W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petr V","family":"Nazarov","sequence":"additional","affiliation":[{"name":"Proteome and Genome Research Unit, Luxembourg Institute of Health , Luxembourg, Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Nicot","sequence":"additional","affiliation":[{"name":"Proteome and Genome Research Unit, Luxembourg Institute of Health , Luxembourg, Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Kreis","sequence":"additional","affiliation":[{"name":"University of Luxembourg, Life Sciences Research Unit\u2014Signal Transduction Laboratory , Belvaux, Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serge","family":"Haan","sequence":"additional","affiliation":[{"name":"University of Luxembourg, Life Sciences Research Unit\u2014Molecular Disease Mechanisms Laboratory , Belvaux, Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iris","family":"Behrmann","sequence":"additional","affiliation":[{"name":"University of Luxembourg, Life Sciences Research Unit\u2014Signal Transduction Laboratory , Belvaux, 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