title: An IL-27/Stat3 axis induces expression of programmed cell death 1 ligands (PD-L1/2) on infiltrating macrophages in lymphoma.
abstract: Immune escape and tolerance in the tumor microenvironment are closely involved in tumor progression, and are caused by T-cell exhaustion and mediated by the inhibitory signaling of immune checkpoint molecules including programmed death-1 (PD-1), cytotoxic T-lymphocyte associated protein 4, and T-cell immunoglobulin and mucin domaincontaining molecule-3. In the present study, we investigated the expression of the PD-1 ligand 1 (PD-L1) in a lymphoma microenvironment using paraffin-embedded tissue samples, and subsequently studied the detailed mechanism of upregulation of PD-L1 on macrophages using cultured human macrophages and lymphoma cell lines. We found that macrophages in lymphoma tissues of almost all cases of adult T-cell leukemia/lymphoma (ATLL), follicular lymphoma and diffuse large B-cell lymphoma expressed PD-L1. Cell culture studies showed that the conditioned medium of ATL-T and SLVL cell lines induced increased expression of PD-L1/2 on macrophages, and that this PD-L1/2 overexpression was dependent on activation of signal transducer and activator of transcription 3 (Stat3). In vitro studies including cytokine array analysis showed that IL-27 (heterodimer of p28 and EBI3) induced overexpression of PD-L1/2 on macrophages via Stat3 activation. Because lymphoma cell lines produced IL-27B (EBI3) but not IL-27p28, it was proposed that the IL-27p28 derived from macrophages and the IL-27B (EBI3) derived from lymphoma cells formed an IL-27 (heterodimer) that induced PD-L1/2 overexpression. Although the significance of PD-L1/2 expressions on macrophages in lymphoma progression has never been clarified, an IL-27-Stat3 axis might be a target for immunotherapy for lymphoma patients.
authors: Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors: Hasita
authors: H
authors: Horlad
authors: Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors: Chaoya
authors: C
authors: Ma
authors: Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors: Hiromu
authors: H
authors: Yano
authors: Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors: Cheng
authors: C
authors: Pan
authors: Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors: Koji
authors: K
authors: Ohnishi
authors: Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors: Yukio
authors: Y
authors: Fujiwara
authors: Department of Hematology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors: Shinya
authors: S
authors: Endo
authors: Department of Hematology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors: Yoshitaka
authors: Y
authors: Kikukawa
authors: Department of Hematology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors: Yutaka
authors: Y
authors: Okuno
authors: Department of Hematology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.|Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Kyoto, Japan.
authors: Masao
authors: M
authors: Matsuoka
authors: Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors: Motohiro
authors: M
authors: Takeya
authors: Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors: Yoshihiro
authors: Y
authors: Komohara
mesh_terms: D060890:B7-H1 Antigen / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000494:pharmacology; D006801:Humans; D007378:Interleukins / Q000378:metabolism*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000276:immunology* / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D015778:Minor Histocompatibility Antigens / Q000378:metabolism*; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; D017077:Culture Media, Conditioned; C097732:EBI3 protein, human; D007378:Interleukins; D015778:Minor Histocompatibility Antigens; D061027:Programmed Cell Death 1 Ligand 2 Protein; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human
keywords: CD163; PD-L1; PD-L2; macrophage; tumor-associated macrophages