Interferon-γ and tumor necrosis factor-α induce an immunoinhibitory molecule, B7-H1, via nuclear factor-κB activation in blasts in myelodysplastic syndromes

Abstract

During disease progression in myelodysplastic syndromes (MDS), clonal blasts gain a more aggressive nature, whereas nonclonal immune cells become less efficient via an unknown mechanism. Using MDS cell lines and patient samples, we showed that the expression of an immunoinhibitory molecule, B7-H1 (CD274), was induced by interferon-␥ (IFN␥) and tumor necrosis factor-␣ (TNF␣) on MDS blasts. This induction was associated with the activation of nuclear factor-B (NF-B) and nearly completely blocked by an NF-B inhibitor, pyrrolidine dithiocarbamate (PDTC). B7-H1 ؉ MDS blasts had greater intrinsic proliferative capacity than B7-H1 ؊ MDS blasts when examined in various assays. Furthermore, B7-H1 ؉ blasts suppressed T-cell proliferation and induced T-cell apoptosis in allogeneic cocultures. When fresh bone marrow samples from patients were examined, blasts from high-risk MDS patients expressed B7-H1 molecules more often compared with those from low-risk MDS patients. Moreover, MDS T cells often overexpressed programmed cell death 1 (PD-1) molecules that transmit an inhibitory signal from B7-H1 molecules. Taken IntroductionB7-H1 (CD274), which was identified by us as a costimulatory molecule, plays a crucial role in T-cell regulation in various immune responses. 1,2 B7-H1 molecules deliver a costimulatory signal through an unknown receptor on naive T cells. [1][2][3] They also deliver an inhibitory signal to activated T cells through programmed cell death 1 (PD-1) molecules, 4 which are a type I transmembrane protein belonging to the CD28 receptor family and were originally identified in T cells undergoing apoptosis. 5 B7-H1 expression is detected not only on antigenpresenting cells but also on activated T cells and some tumor cells (ie, renal cell, colon, breast, and lung carcinoma, and Hodgkin lymphoma). [6][7][8][9][10] Rodent data suggest that B7-H1 molecules on tumor cells deliver negative signals through PD-1 and other receptors on tumorspecific cytotoxic T lymphocytes and inhibit antitumor immune responses. 11,12 Consistent with those data, it was reported that in patients with renal cell carcinoma and breast cancer, patients whose tumor cells expressed B7-H1 had a poor prognosis. 9,13 In a mouse leukemia model in which mice were immunized with irradiated DA1-3b leukemia cells and then challenged with live DA1-3b cells, only leukemia cells expressing high levels of B7-H1 survived for a long period. Moreover, these cells gained tolerance to specific cytotoxic T lymphocytemediated killing. 14 Therefore, B7-H1 molecules on leukemia cells may be associated with immune evasion in this model.Myelodysplastic syndromes (MDS) are clonal hematologic stem cell disorders characterized by cytopenias, excessive apoptosis of hematopoietic cells, and a high risk of progression to acute myeloid leukemia (AML). In MDS, various immune abnormalities, including lymphopenia and T-cell dysfunction, have been reported, 15-17 although data on B7-related molecules, in particular B7-H1, are lacking. With disease progression, that is, with i...

Tumor PD-L1 expression is correlated with increased TILs and poor prognosis in penile squamous cell carcinoma

“…36,37 Extrinsic PD-L1 expression is thought to be induced by cytokines, especially IFNg, in the tumor environment via various downstream pathways. [17][18][19] Because PD-L1 expression in PeSCC cells can be either intrinsic or extrinsic, studies investigating the precise pathways involved are currently underway in our laboratory.…”

“…16 Cytokines, especially interferon-gamma (IFNg), that are expressed by activated T cells can induce PD-L1 expression in the surrounding tumor cells via specific signaling pathways. [17][18][19] To better elucidate the correlation between PD-L1 expression and TILs in PeSCC, the mRNA expression levels of PD-L1, IFNg, and CD8 C were evaluated in 24 primary penile cancer specimens. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) showed a significant positive correlation between PD-L1 and IFNg or CD8 C ( Fig.…”

IL-12 Regulates B7-H1 Expression in Ovarian Cancer-associated Macrophages by Effects on NF-κB Signalling

“…IL-12 can induce IFN-γ expression and secretion of T cells, NK cells and macrophages (Wysocka et al, 1995;Puddu et al, 1997), the promoter region of the human B7-H1 gene has an NF-κB motif ). IFN-γ upregulated B7-H1 expression in some cells via NF-κB signal pathway activation (Kondo et al, 2010;Huang et al, 2013). However, the molecular mechanisms of action regulating the gene expression of B7-H1 vary in both different cell types and distinct stimuli.…”

“…To further explore the possible mechanism of IL-12 exerts function in regulating B7-H1 expression; we investigated the expression of IFN-γ firstly, because IFN-γ has been well known to induce the expression of B7-H1 (Lee et al, 2005;Lee et al, 2006;Kondo et al, 2010). It was found that rIL-12 and Ad-IL-12-GFP treated groups produced a higher level of IFN-γ in the supernatants of monocyte-derived macrophages cocultured with SKOV3 system.…”

Development of Cytogenetic Abnormalities in Myelodysplastic Syndromes

“…With the disease progression, MDS blasts become less apoptotic with increased proliferative capacity, producing phenotypically immature clone of cells, whereas the T-cell compartment shows decreased proliferation and increased apoptosis [27][28][29][30][31][32]. Kondo et al in 2010 showed that the increased production of IFN-γ and TNFα enhances the proliferation of blasts through the expression of B7-H1 on MDS blasts and could be an early event in the disease progression [33]. Additionally, B7-H1 + blasts suppress proliferation of T cells and induce their apoptosis in in vitro co-cultures [33].…”