Yumi Nonomura

Idiopathic thrombocytopenic purpura induced by nivolumab in a metastatic melanoma patient with elevated PD-1 expression on B cells

ABSTRACT Nivolumab has shown promising early results in patients with advanced malignancies, including melanoma and lung cancer, with generally manageable side effects. On the other hand, recent studies showed that the immune activation caused by PD-1 blockade might promote severe autoimmune toxicity. Herein, we report a case of idiopathic thrombocytopenic purpura during nivolumab therapy.

Roles of basophils and mast cells in cutaneous inflammation

Mast cells and basophils are associated with T helper 2 (Th2) immune responses. Newly developed mast cell-deficient mice have provided evidence that mast cells initiate contact hypersensitivity via activating dendritic cells. Studies using basophil-deficient mice have also revealed that basophils are responsible for cutaneous Th2 skewing to haptens and peptide antigens but not to protein antigens. Recently, several studies reported the existence of innate lymphoid cells (ILCs), which differ from classic T cells in that they lack the T cell receptor. Mast cells and basophils can interact with ILCs and play some roles in the pathogenesis of Th2 responses. Basophil-derived interleukin (IL)-4 enhances the expression of the chemokine CCL11, as well as IL-5, IL-9, and IL-13 in ILC2s, leading to the accumulation of eosinophils in allergic reactions. IL-33-stimulated mast cells can play a regulatory role in the development of ILC2-mediated non-antigen-specific protease-induced acute inflammation. In this review, we discuss the recent advances in our understanding of mast cells and basophils in immunity and inflammation.

Tumour hypoxia promotes melanoma growth and metastasis via High Mobility Group Box-1 and M2-like macrophages.

Hypoxia is a hallmark of cancer that is strongly associated with invasion, metastasis, resistance to therapy and poor clinical outcome. Tumour hypoxia affects immune responses and promotes the accumulation of macrophages in the tumour microenvironment. However, the signals linking tumour hypoxia to tumour-associated macrophage recruitment and tumour promotion are incompletely understood. Here we show that the damage-associated molecular pattern High-Mobility Group Box 1 protein (HMGB1) is released by melanoma tumour cells as a consequence of hypoxia and promotes M2-like tumour-associated macrophage accumulation and an IL-10 rich milieu within the tumour. Furthermore, we demonstrate that HMGB1 drives IL-10 production in M2-like macrophages by selectively signalling through the Receptor for Advanced Glycation End products (RAGE). Finally, we show that HMGB1 has an important role in murine B16 melanoma growth and metastasis, whereas in humans its serum concentration is significantly increased in metastatic melanoma. Collectively, our findings identify a mechanism by which hypoxia affects tumour growth and metastasis in melanoma and depict HMGB1 as a potential therapeutic target.

Peripheral blood Th9 cells are a possible pharmacodynamic biomarker of nivolumab treatment efficacy in metastatic melanoma patients

ABSTRACT Although nivolumab is associated with a significant improvement in overall survival and progression-free survival, only 20 to 40% of patients experience long-term benefit. It is therefore of great interest to identify a predictive marker of clinical benefit for nivolumab. To address this issue, the frequencies of CD4+ T cell subsets (Treg, Th1, Th2, Th9, Th17 and Th22), CD8+ T cells, and serum cytokine levels (IFNγ, IL-4, IL-9, IL-10, TGF-β) were assessed in 46 patients with melanoma. Eighteen patients responded to nivolumab, and the other 28 patients did not. An early increase in Th9 cell counts during the treatment with nivolumab was associated with an improved clinical response. Before the first nivolumab infusion, the responders displayed elevated serum concentrations of TGF-β compared to non-responders. Th9 induction by IL-4 and TGF-β was enhanced by PD-1/PD-L1 blockade in vitro. The role of IL-9 in disease progression was further assessed using a murine melanoma model. In vivo IL-9 blockade promoted melanoma progression in mice using an autochthonous mouse melanoma model, and the cytotoxic ability of murine melanoma-specific CD8+ T cells was enhanced in the presence of IL-9 in vitro. These findings suggest that Th9 cells, which produce IL-9, play an important role in the successful treatment of melanoma patients with nivolumab. Th9 cells therefore represent a valid biomarker to be further developed in the setting of anti-PD-1 therapy.

ADAMTSL5 is upregulated in melanoma tissues in patients with idiopathic psoriasis vulgaris induced by nivolumab

Editor The monoclonal antibody nivolumab, which blocks programmed cell death 1 (PD-1) expressed on activated CD8 T cells, is associated with a significant improvement in overall survival in patients with advanced melanoma. Recent studies have shown that the immune activation caused by PD-1 blockade might promote autoimmune toxicity, such as colitis, thyroiditis and psoriasis vulgaris. In psoriasis vulgaris, autoantigens in the epidermis had been considered as the target of clonal CD8 T cells; however, the target cells and antigens that drive pathogenic CD8 T-cell responses in psoriasis lesions remained unproven. A recent study demonstrated that a disintegrin and metalloproteinase with thrombospondin motifs-like 5 (ADAMTSL5), which is expressed in melanocytes in the epidermis, is one of the antigens that trigger the autoimmunity in psoriasis. Herein, we analysed the expression of ADAMTSL-5 in melanoma tissues in three cases of melanoma patients who had developed or exacerbated psoriasis vulgaris during nivolumab treatment. Using immunofluorescence as reported previously, we investigated the expression of ADAMTSL5 and CD3 of the melanoma tissues of three Japanese patients who developed or had exacerbated psoriasis vulgaris after nivolumab administration. Melanoma tissues from those who did not develop psoriasis vulgaris or had it exacerbated, were investigated as controls. The patients were diagnosed with psoriasis by dermatopathologists on the basis of pathological findings. Detailed information of the patients is shown in Table S1. In the melanoma patients with psoriasis after nivolumab injection, both the expression of ADAMTSL5 and the infiltration of CD3 cells were observed at the melanoma tissues (Fig. 1a, b and c). CD3 cells were located adjacent to ADAMTSL5-positive cells (Fig . 1c, high magnification). As control patients, we examined melanoma patients who were treated with nivolumab but did not develop psoriasis. We did not find the co-localization of ADAMTSL5 and CD3 in the melanoma tissues (Fig. 1d and Table S1). The human leucocyte antigen (HLA) class I allele, HLAC*06:02, is known as the main psoriasis risk gene. ADAMTSL5 was identified as an HLA-C*06:02-presented melanocytic autoantigen of the Va3S1/Vb13S1 T-cell receptor (TCR). As such, we investigated the HLA genotype of our patients, but they exhibited different genotypes, and none of them corresponded with HLA-C*06:02. (data not shown). In this study, high expression levels of ADAMTSL5 were observed in Japanese patients who developed psoriasis or had it exacerbated after nivolumab administration. In addition, the infiltration of CD3 cells adjacent to ADAMTSL5-positive cells was observed. Recently, Arakawa et al. have reported that some melanocytes in the epidermis express ADAMTSL5 and that ADAMTSL5-specific CD8 T cells trigger the immune response that consequently results in psoriasis. We believe that ADAMTSL5-specific T cells were activated, which triggered the psoriatic immune response in our three cases. It appears that the HLA genotype or antigen type was not involved in the present cases. Our study suggests that the expression of ADAMTSL5 in melanoma lesions may be a biomarker that predicts psoriasis as an adverse effect of nivolumab administration.

Baseline neutrophil to lymphocyte ratio combined with serum lactate dehydrogenase level associated with outcome of nivolumab immunotherapy in a Japanese advanced melanoma population

Although immune checkpoint inhibitors (ICI) significantly improve the survival of advanced melanoma, more than half of the patients received no benefit. To predict outcomes, efforts to associate baseline peripheral blood biomarkers were started in patients given treatment with ipilimumab. Among the most critical markers is an increased neutrophil-to-lymphocyte ratio (NLR), which negatively correlates with outcome. Although several baseline factors have been reported to correlate with outcome in patients treated with nivolumab/pembrolizumab (eosinophil count, lymphocyte count, lactate dehydrogenase [LDH], and c-reactive protein [CRP]), a positive link between NLR and outcome has yet to be shown. This article is protected by copyright. All rights reserved.

Biomarkers for evaluation of mast cell and basophil activation

Mast cells and basophils play a pathogenetic role in allergic, inflammatory, and autoimmune disorders. These cells have different development, anatomical location and life span but share many similarities in mechanisms of activation and type of mediators. Mediators secreted by mast cells and basophils correlate with clinical severity in asthma, chronic urticaria, anaphylaxis, and other diseases. Therefore, effective biomarkers to measure mast cell and basophil activation in vivo could potentially have high diagnostic and prognostic values. An ideal biomarker should be specific for mast cells or basophils, easily and reproducibly detectable in blood or biological fluids and should be metabolically stable. Markers of mast cell and basophil include molecules secreted by stimulated cells and surface molecules expressed upon activation. Some markers, such as histamine and lipid mediators are common to mast cells and basophils whereas others, such as tryptase and other proteases, are relatively specific for mast cells. The best surface markers of activation expressed on mast cells and basophils are CD63 and CD203. While these mediators and surface molecules have been associated to a variety of diseases, none of them fulfills requirements for an optimal biomarker and search for better indicators of mast cell/basophil activation in vivo is ongoing.

Up-regulation of Activation Markers on Basophils in Patients with Papuloerythroderma

Papuloerythroderma is a pruritic eruption of flat-topped papules in a background of erythroderma that characteristically spares skin folds; so-called “deck-chair sign” (1). Histopathology reveals a non-specific spongiotic dermatitis-like pattern, such as slight epidermal hyperplasia with spongiosis and a primarily perivascular dermal infiltrate with lymphocytes, histiocytes and eosinophils. Peripheral eosinophilia and elevated serum immunoglobulin E (IgE) are detected in most cases of papuloerythroderma. Recent studies have shown that basophils play some roles in the pathogenesis of cutaneous allergic diseases, where eosinophils are present, by functioning as initiator cells. CD63, CD69, and CD203c are basophil activation markers that are known to be upregulated by cross-linking of the FcɛRIα receptor. They may serve as useful activation markers in several diseases, including chronic urticaria and prurigo (2). A previous study revealed that basophil-derived interleukin (IL)-4 promotes antigen-specific T helper (Th)2 cell differentiation (3). However, it remains unknown whether basophils mediate the pathological mechanisms in papuloerythroderma. We report here 2 cases of papuloerythroderma that exhibited infiltration of basophils with upregulation of activation markers.

Sarcoidosis of the scalp presenting as patchy alopecia; analysis of transforming growth factor-β expression in the affected area by immunostaining

ejd.2012.1910 Auteur(s) : Yumi Nonomura, Atsushi Otsuka otsukamn@kuhp.kyoto-u.ac.jp, Yoshiki Miyachi, Kenji Kabashima kaba@kuhp.kyoto-u.ac.jp Department of Dermatology, Kyoto University Graduate School of Medicine 54 Shogoin-Kawara, Sakyo Kyoto 606-8507, Japan Sarcoidosis is a systemic granulomatous disease with a predilection for the lungs, lymph nodes, liver, eyes, and skin [1]. Cutaneous lesions are present in 20-35% of cases with systemic sarcoidosis, whereas nearly 25% of patients have only [...]

Female pattern hair loss possibly caused by tamoxifen: Androgen receptor expression in the outer root sheath in the affected area

However, our case was free from photophobia and mental retardation. There is one report in which biopsied alopecia of CHH was examined to show pseudopelade with fibrous cords reaching the epidermis, orphaned hair muscles, orthohyperkeratosis and the absence of normal hair follicles. In contrast to the previous one, we identified two intriguing findings. First, we found normal hair follicles and partly thinned and partly thickened epidermis, which can be explained by mosaicism at a microscopic level. Second, we found that lymphocytes infiltrated sebaceous glands as well as perivascular and perifollicular areas. This finding implies that development of alopecia in CHH syndrome may involve inflammation. According to Al-Zaid et al., loss of sebaceous glands is an early finding among scarring alopecia (SA), and inflammation of sebaceous gland and/or duct may play a role in initiating or accelerating follicular damage during the development of SA. They also suggested that duct obstruction by the damaged duct cells leads to sebaceous gland inflammation and dysfunction. Although we did not observe active hair loss accompanying apparent cytotoxic damage, we speculate that the inflammation may play a role in the development of hair loss in CHH syndrome. To summarize, this is the report of alopecia in CHH syndrome with precise histological observations. More reports are needed to clarify the underlying pathomechanism and treat alopecia of CHH syndrome.