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.
Highlights
Diffuse large B cell lymphoma (DLBCL) is the most common type of aggressive non-Hodgkin’s lymphoma (NHL) and accounts for 30%–40% of NHLs in adults [1]
We investigated the percentage of Th17 cells in peripheral blood mononuclear cells (PBMCs) and in tumor-infiltrating lymphocytes (TILs) from 20 newly diagnosed diffuse large B cell lymphoma (DLBCL) patients (Table 1) and 20 healthy volunteers
The mean Th17 cells percentage was significantly lower in the PBMCs of DLBCL patients than in those of healthy volunteers (Figure 1B; P = 0.012)
Summary
Diffuse large B cell lymphoma (DLBCL) is the most common type of aggressive non-Hodgkin’s lymphoma (NHL) and accounts for 30%–40% of NHLs in adults [1]. DLBCL consists of a group of malignancies with high heterogeneity in their clinical features, morphology, pathology, genetics, and prognosis [2, 3]. The International Prognostic Index (IPI) is a currently commonly used index to evaluate the clinical prognosis of DLBCL patients. Many DLBCL patients with the same IPI scores have different prognoses, especially those with low IPI scores [6]. The IPI is mainly composed of clinical characteristics, and does not include the molecular pathology of DLBCL [6]. The pathogenesis of DLBCL, especially the immunological pathogenesis of the DLBCL microenvironment, remains elusive. Exploring the molecular mechanism and searching for new prognostic markers of DLBCL is an important focus topic for clinical scientists
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