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      Increased expression of IRF8 in tumor cells inhibits the generation of Th17 cells and predicts unfavorable survival of diffuse large B cell lymphoma patients

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          Abstract

          The immunological pathogenesis of diffuse large B cell lymphoma (DLBCL) remains elusive. Searching for new prognostic markers of DLBCL is a crucial focal point for clinical scientists. The aim of the present study was to examine the prognostic value of interferon regulatory factor 8 (IRF8) expression and its effect on the development of Th17 cells in the tumor microenvironment of DLBCL patients. Flow cytometry, immunohistochemistry, and quantitative real-time PCR were used to detect the distribution of Th17 cells and related cytokines and IRF8 in tumor tissues from DLBCL patients. Two DLBCL cell lines (OCI-LY10 and OCI-LY1) with IRF8 knockdown or overexpression and two human B lymphoblast cell lines were co-cultured with peripheral blood mononuclear cells (PBMCs) in vitro to determine the effect of IRF8 on the generation of Th17 cells. Quantitative real-time PCR and Western blotting were used to investigate the involvement of retinoic acid receptor-related orphan receptor gamma t (RORγt) in the effect of IRF8 on Th17 cell generation. The survival of 67 DLBCL patients was estimated using the Kaplan-Meier method and log-rank analysis. The percentage of Th17 cells was lower in DLBCL tumor tissues than in PBMCs and corresponding adjacent benign tissues. Relative expression of interleukin (IL)-17A was lower, whereas that of interferon (IFN)-γ was higher in tumor tissues than in benign tissues. Co-culture with DLBCL cell lines inhibited the generation of Th17 cells in vitro. IRF8 upregulation was detected in DLBCL tumor tissues, and it was associated with decreased DLBCL patient survival. Investigation of the underlying mechanism suggested that IRF8 upregulation in DLBCL, through an unknown mechanism, inhibited Th17 cell generation by suppressing RORγt in neighboring CD4+ T cells. Tumor cells may express soluble or membrane-bound factors that inhibit the expression of RORγt in T cells within the tumor microenvironment. Our findings suggest that IRF8 expression could be a prognostic factor for DLBCL.

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          Most cited references43

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          Diffuse large B-cell lymphoma: current strategies and future directions.

          Diffuse large B-cell lymphoma (DLBCL) is the most common histology of non-Hodgkin lymphoma, representing 25% to 35% of new cases annually. The incidence of DLBCL has doubled in the past decades, highlighting the need for more effective treatment regimens. This article reviews the current protocols applicable to this aggressive lymphoma and discusses ongoing research that is focusing on molecular diagnostics, prognostic factors have also been defined for DLBCL. Patients with DLBCL vary in clinical presentation, prognosis, and response to current therapies. While current therapy in the rituximab era has led to improved outcomes with reduced toxicity, novel treatment approaches for localized, advanced, and relapsed/refractory DLBCL are being pursued in clinical trials. Several studies have shown promise, such as trials involving proteasome inhibitors, lenalidomide, and antibody drug conjugates. Recent discoveries in the spectrum of care for patients with DLBCL have prompted a renaissance for personalized cancer medicine and molecularly targeted therapy. Potential targets and novel drug combinations are undergoing continued study in the hope of achieving successful and personalized care of this disease.
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            Diffuse large B-cell lymphoma.

            Diffuse large B-cell lymphoma is the most common lymphoma worldwide. Both morphologically and prognostically it represents a diverse spectrum of disease. Traditional morphologic subclassification often results in poor interobserver reproducibility and has not been particularly helpful in predicting outcome. Recent gene expression profiling studies have classified diffuse large B-cell lymphoma into 2 main subtypes, germinal center B-cell and activated B-cell, with the germinal center type showing an overall better survival. Validation of these subtypes has become possible for the practicing pathologist with the use of surrogate immunohistochemical markers. Importantly however, these prognostic studies were performed on material from the pre-rituximab treatment era. With the now well-accepted addition of rituximab (anti-CD20 antibody) to the typical large B-cell lymphoma chemotherapeutic regimen, a revalidation of any survival differences between the large B-cell lymphoma subgroups is necessary. This short review covers the current clinical, morphologic, immunophenotypic, genetic, gene expression profiling, and prognostic (studies before and after the addition of rituximab) features of de novo diffuse large B-cell lymphoma.
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              Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells

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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                25 July 2017
                8 May 2017
                : 8
                : 30
                : 49757-49772
                Affiliations
                1 Department of Hematology & Oncology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China
                2 Department of Hematology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China
                3 Immunology Institute, Mount Sinai School of Medicine, New York, NY, USA
                4 Department of Pathology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China
                5 Department of Laboratory, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China
                6 Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangdong Esophageal Cancer Institute, Cancer Center, Sun Yat-Sen University, Guangzhou, China
                Author notes
                Correspondence to: Qingshan Li, drliqingshang@ 123456126.com
                Article
                17693
                10.18632/oncotarget.17693
                5564805
                28537908
                2dc38923-2312-48ae-9eac-df996747c11f
                Copyright: © 2017 Zhong et al.

                This article is distributed under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 26 October 2016
                : 18 April 2017
                Categories
                Research Paper

                Oncology & Radiotherapy
                interferon regulatory factor 8,th17 cells,lymphoma,large b cell,diffuse
                Oncology & Radiotherapy
                interferon regulatory factor 8, th17 cells, lymphoma, large b cell, diffuse

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