TY - JOUR
T1 - The PD-L1- and IL6-mediated dampening of the IL27/STAT1 anticancer responses are prevented by α-PD-L1 or α-IL6 antibodies
AU - Rolvering, Catherine
AU - Zimmer, Andreas D.
AU - Ginolhac, Aurélien
AU - Margue, Christiane
AU - Kirchmeyer, Mélanie
AU - Servais, Florence
AU - Hermanns, Heike M.
AU - Hergovits, Sabine
AU - Nazarov, Petr V.
AU - Nicot, Nathalie
AU - Kreis, Stephanie
AU - Haan, Serge
AU - Behrmann, Iris
AU - Haan, Claude
N1 - Funding Information:
This work was supported by the University of Luxembourg Grants “Meta-IL6 and IL6LongLiv” and the Fonds National de la Recherche (FNR) Grant C12/BM/3975937 (“HepmiRSTAT“). The work of H.M.H. /S.H. was supported by the Grant FZ82 of the Deutsche Forschungs Gemeinschaft (DFG). We thank Demetra Philippidou for excellent technical assistance and Sebastien Plançon for his expert help concerning flow cytometry. We also thank our collaborator Prof. Dr. Nobuyuki Kato (Department of Molecular Biology, Okayama University, Japan) for providing the PH5CH8 cells; Prof. Dr. Stefan Rose-John (University of Kiel, Germany) for providing hyper-IL6; and Prof. Jan Tavernier for providing the rPAP reporter gene construct.
Funding Information:
All authors approve to the publication of this paper. C.R. performed and planned experiments and wrote the paper. A.D.Z., C.M., D.P., M.K., F.S., S.H., and N.N. performed and planed experiments. A.G. and P.V.N. performed bioinformatic analysis. S.K., H.M.H., S.H., I.B., and C.H. planned experiments and wrote the paper. Datasets supporting the conclusions of this article are included within the article and its additional file. Microarray raw data were deposited in the ArrayExpress public repository with the reference number E-MTAB-6080. This work was supported by the University of Luxembourg Grants “Meta-IL6 and IL6LongLiv” and the Fonds National de la Recherche (FNR) Grant C12/BM/3975937 (“HepmiRSTAT“). The work of H.M.H. /S.H. was supported by the Grant FZ82 of the Deutsche Forschungs Gemeinschaft (DFG). We thank Demetra Philippidou for excellent technical assistance and Sebastien Plançon for his expert help concerning flow cytometry. We also thank our collaborator Prof. Dr. Nobuyuki Kato (Department of Molecular Biology, Okayama University, Japan) for providing the PH5CH8 cells; Prof. Dr. Stefan Rose-John (University of Kiel, Germany) for providing hyper-IL6; and Prof. Jan Tavernier for providing the rPAP reporter gene construct. The authors declare no conflicts of interest.
Publisher Copyright:
©2018 The Authors. Society for Leukocyte Biology Published by Wiley Periodicals, Inc.
PY - 2018/11
Y1 - 2018/11
N2 - Interleukin-27 (IL27) is a type-I cytokine of the IL6/IL12 family and is predominantly secreted by activated macrophages and dendritic cells. 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-γ-like response in the microarray analyses, with up-regulation of genes involved in antiviral defense, antigen presentation, and immune suppression. Like IFN-γ, 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-γ. 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 T H 1 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—mimicking a situation occurring, for example, in IL6-secreting tumors or in tumor inflammation–induced cachexia—can 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.
AB - Interleukin-27 (IL27) is a type-I cytokine of the IL6/IL12 family and is predominantly secreted by activated macrophages and dendritic cells. 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-γ-like response in the microarray analyses, with up-regulation of genes involved in antiviral defense, antigen presentation, and immune suppression. Like IFN-γ, 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-γ. 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 T H 1 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—mimicking a situation occurring, for example, in IL6-secreting tumors or in tumor inflammation–induced cachexia—can 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.
KW - IDO-1
KW - IFN-γ
KW - OSM
KW - cytokine
KW - interferon
UR - http://www.scopus.com/inward/record.url?scp=85055077312&partnerID=8YFLogxK
U2 - 10.1002/JLB.MA1217-495R
DO - 10.1002/JLB.MA1217-495R
M3 - Article
C2 - 30040142
AN - SCOPUS:85055077312
SN - 0741-5400
VL - 104
SP - 969
EP - 985
JO - Journal of Leukocyte Biology
JF - Journal of Leukocyte Biology
IS - 5
ER -