H. Kamijo

Serum vascular endothelial growth factor A levels reflect itch severity in mycosis fungoides and Sézary syndrome

Angiogenesis is an important step to support progression of malignancies, including mycosis fungoides (MF) and Sézary syndrome (SS). Vascular endothelial growth factor (VEGF)‐A, a key player in angiogenesis, is secreted by tumor cells of MF/SS and its expression levels in lesional skin correlated with disease severity. In this study, we examined serum VEGF‐A levels in MF/SS patients. Serum VEGF‐A levels were elevated in patients with erythrodermic MF/SS and the levels decreased after treatment. Importantly, serum VEGF‐A levels positively correlated with markers for pruritus. We also found that VEGF‐A upregulated mRNA expression of thymic stromal lymphopoietin by keratinocytes. Taken together, our study suggests that VEGF‐A can promote progression and pruritus in MF/SS. Inhibition of VEGF‐A signaling can be a therapeutic strategy for patients with erythrodermic MF/SS.

Decreased IL-10-producing regulatory B cells in patients with advanced mycosis fungoides

BackgroundHistorically, B cells have been considered as positive regulators of humoral immune responses. Specific B-cell subsets, however, negatively regulate immune responses and are termed “regulatory B cells” (Bregs). Recently, Bregs have been linked to not only inflammatory and autoimmune diseases, but also malignancies via suppressing antitumour immunity.ObjectivesTo investigate the involvement of Bregs in advanced mycosis fungoides (MF).Materials&MethodsThe frequency ofCD19+CD24hiCD27+ memoryBcells andCD19+CD24hiCD38hi transitional B cells (which enrich IL-10-producing Bregs) was examined in peripheral blood from patients with advanced MF (n = 11) and healthy controls (n = 9) by flow cytometry. The frequency of IL-10-producing Bregs was also measured by flow cytometry. The correlation between frequency or number of B-cell subsets and disease severity markers was also analysed.ResultsThe frequency of CD19+CD24hiCD27+ B cells, CD19+CD24hiCD38hi B cells, and IL-10-producing B cells was decreased in peripheral blood of advanced MF patients. The frequency and number of these B-cell subsets inversely correlated with serum soluble IL-2 receptor and serum lactate dehydrogenase levels.ConclusionsThe development of IL-10-producing Bregs is impaired in patients with advanced MF and a decrease in IL-10-producing Bregs may play an important role in the progression of advanced MF.

Aberrant CD137 ligand expression induced by GATA6 overexpression promotes tumor progression in cutaneous T-cell lymphoma

CD137 and its ligand, CD137L, are expressed on activated T cells and antigen-presenting cells, respectively. Recent studies have shown that CD137L and CD137 are aberrantly expressed by tumor cells, especially in some hematopoietic malignancies, and interactions between these molecules on tumor cells promote tumor growth. In this study, we investigated the roles of CD137L and CD137 in cutaneous T-cell lymphoma (CTCL), represented by mycosis fungoides and Sézary syndrome. Flow cytometric analysis showed that primary Sézary cells and CTCL cell lines (Hut78, MyLa, HH, SeAx, and MJ) aberrantly expressed CD137L. CD137L expression by tumor cells in CTCL was also confirmed by immunohistochemistry. Anti-CD137L-neutralizing antibody inhibited proliferation, survival, CXCR4-mediated migration, and in vivo growth in CTCL cell lines through inhibition of phosphorylation of AKT, extracellular signal-regulated kinase 1/2, p38 MAPK, and JNK. Moreover, suppression of CD137L signaling decreased antiapoptotic proteins Bcl-2 and phosphorylated Bad. We also explored the transcription factor regulating CD137L expression. Because GATA6 has been proposed as an oncogene in many types of tumors with aberrant CD137L expression, we examined GATA6 expression and the involvement of GATA6 in CD137L expression in CTCL. DNA hypomethylation and histone acetylation induced GATA6 overexpression in CTCL cells. Furthermore, chromatin immunoprecipitation, luciferase reporter assay, and knockdown by short hairpin RNA showed that GATA6 directly upregulated CD137L expression. Inhibition of GATA6 resulted in decreased survival and in vivo growth in CTCL cells. Collectively, our findings prompt a novel therapeutic approach to CTCL based on the discovery that the GATA6/CD137L axis plays an important role in the tumorigenesis of CTCL.

BET bromodomain inhibitor JQ1 decreases CD30 and CCR4 expression and proliferation of cutaneous T-cell lymphoma cell lines

Bromodomain and external domain (BET) proteins regulate cell growth, proliferation, cell cycle, and differentiation in various cancers. Therefore, they have emerged as interesting targets. The effect of BET inhibitor on cutaneous T-cell lymphoma (CTCL), however, is yet to be known. Here, we examined the effect of BET inhibitor JQ1 on four cell lines (MyLa, SeAx, Hut78 and HH cells). CTCL cell lines were treated with JQ1 and cell number, cell cycle, frequency of apoptosis, and expressions of CD25, CD30 and CCR4 on the cell surface were evaluated by flow cytometry. Cell surface molecules were also analyzed by quantitative RT-PCR. JQ1 dose-dependently decreased the cell number of CTCL cells through G1 arrest concomitantly with downregulation of c-Myc expression. JQ1 induced senescence in MyLa cells and apoptosis in Hut78 and HH cells. We also showed that JQ1 inhibited tumor growth of HH cells in vivo. Moreover, JQ1 downregulated CD30 and CCR4 expression both on the cell surface and at mRNA levels. Thus, BET bromodomain inhibitor JQ1 may be useful for treatment of CTCL.