Takanori Hidaka

The aryl hydrocarbon receptor AhR links atopic dermatitis and air pollution via induction of the neurotrophic factor artemin

Atopic dermatitis is increasing worldwide in correlation with air pollution. Various organic components of pollutants activate the transcription factor AhR (aryl hydrocarbon receptor). Through the use of AhR-CA mice, whose keratinocytes express constitutively active AhR and that develop atopic-dermatitis-like phenotypes, we identified Artn as a keratinocyte-specific AhR target gene whose product (the neurotrophic factor artemin) was responsible for epidermal hyper-innervation that led to hypersensitivity to pruritus. The activation of AhR via air pollutants induced expression of artemin, alloknesis, epidermal hyper-innervation and inflammation. AhR activation and ARTN expression were positively correlated in the epidermis of patients with atopic dermatitis. Thus, AhR in keratinocytes senses environmental stimuli and elicits an atopic-dermatitis pathology. We propose a mechanism of air-pollution-induced atopic dermatitis via activation of AhR.

Comparison of Foxp3+ regulatory T cells and CD163+ macrophages in invasive and non-invasive extramammary Paget's disease.

Regulatory T cells (Tregs), identified by the expression of CD4, CD25 and Foxp3, together with immunosuppressive macrophages, such as CD163+ M2 macrophages, are involved in maintaining peripheral tolerance. The aim of this study was to elucidate the involvement of Tregs and CD163+ macrophages in invasive and non-invasive extramammary Pagets disease. The presence of CD4+CD25+Foxp3+ Tregs, CD163+ M2 macrophages and matrix metalloproteinase-9+ cells was examined immunohistologically in fixed sections of lesional skin from 10 patients with non-invasive extramammary Pagets disease and 7 patients with invasive extramammary Pagets disease. Fewer CD4+CD25+Foxp3+ Tregs were observed in non-invasive extramammary Pagets disease than in invasive extramammary Pagets disease. In contrast, higher numbers of CD163+ macrophages and metalloproteinase-9+ cells were detected only in invasive extramammary Pagets disease. These findings suggest that the induction of immunosuppressive cells in extramammary Pagets disease differs according to the tumour stage.

Tumor-associated M2 macrophages in mycosis fungoides acquire immunomodulatory function by interferon alpha and interferon gamma

BACKGROUND Tumor-associated M2 macrophages (TAMs) produce chemokines that affect the formation of cutaneous T-cell lymphoma (CTCL) by stromal factors. Since IFNs are an effective treatment for advanced-stage mycosis fungoides (MF), we hypothesized that IFNs might modulate M2 macrophages. OBJECTIVE To prove our hypothesis, we stimulated monocyte-derived M2 macrophages with IFN-α2a or IFN-γ and examined the mRNA expression of chemokines. METHODS By using a microarray, we selected a series of chemokines and MMPs that were strongly connected with the IL-4 stimulation. Then, we investigated the effects of IFN-α2a and IFN-γ on these chemokines. RESULTS IFN-α2a and IFN-γ decreased the expression and production of CCL17 and CCL18 and increased those of CXCL10 and CXCL11. Moreover, the subcutaneous administration of IFN-α2a increased the CXCL11-producing cells in the lesional skin of patients with advanced MF. CONCLUSION Our data suggest one possible mechanism of the therapeutic effects of IFNs through TAMs for the treatment of advanced-stage MF.

A synthetic NOD2 agonist, muramyl dipeptide (MDP)-Lys (L18) and IFN-β synergistically induce dendritic cell maturation with augmented IL-12 production and suppress melanoma growth

BACKGROUND A synthetic NOD2 agonist, muramyl dipeptide (MDP)-Lys (L18), mimics the bacterial peptidoglycan moiety and acts as a powerful adjuvant that induces cell-mediated immunity. OBJECTIVE To investigate the induction of antitumor immune response for malignant melanoma by IFN-β in combination with MDP-Lys (L18) (IFN-MDP-Lys (L18)). METHODS Human monocyte-derived DCs (MoDCs) are stimulated with IFN-MDP-Lys (L18) in vitro. We assess the expression of costimulatory molecules on MoDCs by FACS. Moreover, we investigate the induction of Th1 cytokines by real time PCR and ELISA. Further to confirm the anti tumor immune response of IFN-MDP-Lys (L18) therapy, we examine the growth of B16F10 melanoma in vivo. RESULTS The stimulation of human MoDCs with IFN-MDP-Lys (L18) significantly augmented the production of IL-12p70, TNF-α, and IL-6 compared to that with MDP or that with IFN-β alone. IFN-MDP-Lys (L18) increased the expression of IL-12p35, IL-12p40, IL-10, TNF-α, IL-6 and IL-1β mRNA by MoDC using real-time PCR. The expression of CD83 and costimulatory molecules CD40, CD80, and CD86 was also augmented in MoDC treated with IFN-MDP-Lys (L18), which resulted in their augmented allogeneic T cell stimulation. In vivo, the administration of IFN-MDP-Lys (L18) significantly suppressed the growth of B16F10 melanoma, while the monotherapy of IFN-β or MDP-Lys (L18) did not significantly affect the tumor growth. CONCLUSION These findings suggest that IFN-MDP-Lys (L18) can be a promising adjuvant therapy for malignant melanoma.

Dermoscopy findings of pseudolymphomatous folliculitis.

Pseudolymphomatous folliculitis (PLF), which clinically mimicks cutaneous lymphoma, is a rare manifestation of cutaneous pseudolymphoma and cutaneous lymphoid hyperplasia. Here, we report on a 45-year-old Japanese woman with PLF. Dermoscopy findings revealed prominent arborizing vessels with small perifollicular and follicular yellowish spots and follicular red dots. A biopsy specimen also revealed dense lymphocytes, especially CD1a+ cells, infiltrated around the hair follicles. Without any additional treatment, the patient’s nodule rapidly decreased. The presented case suggests that typical dermoscopy findings could be a possible supportive tool for the diagnosis of PLF.

Isolated adrenocorticotropic hormone deficiency possibly caused by nivolumab in a metastatic melanoma patient.

Dear Editor, Although nivolumab significantly prolongs survival in patients with metastatic melanoma, severe adverse events sometimes occur. Therefore, to predict adverse events from nivolumab is of great interest. This study was approved by the ethics committee of Tohoku University Graduate School of Medicine, Sendai, Japan (20151-731). A 68-year-old Japanese man visited us with multiple nodules on his left foot. He had been treated for acral lentiginous melanoma and had undergone excision of the tumors 3 years prior. Physical examination revealed multiple, skincolored, dome-shaped nodules on his left lower extremities (Fig. 1a). A biopsy specimen revealed dense infiltration of spindle-shaped atypical cells with pigmentation in dermis (Fig. 1b). We diagnosed this patient as having in-transit melanoma, and administrated nivolumab at 2 mg/kg every 3 weeks. Six months after the administration of nivolumab, follow-up magnetic resonance imaging (MRI) revealed multiple brain metastases. Then, we employed a CyberKnife (Accuray, Sunnyvale, CA, USA) (14 Gy in five fractions). One month after finishing the irradiation, the serum thyroid-stimulating hormone level was 7.07 lIU/mL (normal range, 0.50–5.00), though the serum free T3 and T4 were within normal ranges. Because we suspected hypopituitarism, we performed corticotropin-releasing hormone load test, which revealed decreased levels of the serum adrenocorticotropic hormone (ACTH; <1.0 ng/mL) and cortisol (<0.8 lg/dL). Thyrotropin-releasing hormone load test, growth hormone-releasing peptide-2 load test, prolactin test and luteinizing hormone–releasing hormone load test were within normal range. MRI revealed a normally shaped pituitary. Because decreased level of ACTH had been observed in a clinical course of treatment by nivolumab, we diagnosed this patient with isolated ACTH deficiency possibly caused by nivolumab. To further analyze the mechanisms resembling hypophysitis, we retrospectively analyzed the serum soluble (s) CD163, CXCL5 and tumor necrosis factor (TNF)-a. Compared with the serum from seven cases of nivolumab-treated patients without adverse events, our present case showed strikingly upregulated serum levels of sCD163 (Fig. 1c) and CXCL5 (Fig. 1d) 6 weeks after the administration of nivolumab. The serum TNF-a was not detected in all cases. Because nivolumab significantly prolongs survival in melanoma patients, the number of patients administrated nivolumab is increasing. While several reagents were reported to

Possible mechanisms of the crosstalk between Langerhans cells and regulatory T cells in extramammary Paget disease by receptor activator of nuclear factor kappa B (RANK) ligand/RANK pathways.

Extramammary Paget disease (EMPD) is a skin adenocarcinoma of apocrine gland origin, in which Paget cells express receptor activator of nuclear factor kappa B (RANK) ligand (RANKL) and matrix metalloproteinase (MMP)‐7, and release soluble (s)RANKL into the tumour microenvironment. We previously reported that about 60% of the RANK+ cells among the stromal cells are M2 macrophages, but the identity of the remaining population of RANK+ cells is still unknown.

Successful Treatment of HER-2-Positive Metastatic Apocrine Carcinoma of the Skin with Lapatinib and Capecitabine

© 2012 The Authors. doi: 10.2340/00015555-1354 Journal Compilation

Tumor-Associated Macrophages: Therapeutic Targets for Skin Cancer

Tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) are significant components of the microenvironment of solid tumors in the majority of cancers. TAMs sequentially develop from monocytes into functional macrophages. In each differentiation stage, TAMs obtain various immunosuppressive functions to maintain the tumor microenvironment (e.g., expression of immune checkpoint molecules, production of Treg-related chemokines and cytokines, production of arginase I). Although the main population of TAMs is immunosuppressive M2 macrophages, TAMs can be modulated into M1-type macrophages in each differential stage, leading to the suppression of tumor growth. Because the administration of certain drugs or stromal factors can stimulate TAMs to produce specific chemokines, leading to the recruitment of various tumor-infiltrating lymphocytes, TAMs can serve as targets for cancer immunotherapy. In this review, we discuss the differentiation, activation, and immunosuppressive function of TAMs, as well as their benefits in cancer immunotherapy.

Receptor activator of nuclear factor kappa-B ligand (RANKL)/RANK signaling promotes cancer-related inflammation through M2 macrophages.

therefore provide a predisposing environment with a lowered threshold for mechanical stress-induced keratinocyte proliferation. So, the investigations of Plewig may therefore provide experimental data to describe the role of mechanical stress in the development of HS. Acknowledgement The Authors would like to thank Gerd Plewig for his kind and constructive comments to the manuscript. Author contribution JB and GBEJ contributed equally to the generation of the hypothesis, review of the literature, discussion of the data and the writing and revision of the manuscript. Conflicts of interest J. Boer: Advisory board: Abbvie; G.B.E Jemec: Grants: AbbVie, Leo Pharma; Advisory boards: AbbVie, Janssen-Cilag, MSD, Novartis; Investigator: AbbVie, Novartis, Regeneron; Speaker: AbbVie, Boehringer-Ingelheim, MSD. Supporting Information