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Environmental pollution is one of the most serious challenges to health in the modern world. Pollutants alter immune responses and can provoke immunotoxicity. In this Review, we summarize the major environmental pollutants that are attracting wide-ranging concern and the molecular basis underlying their effects on the immune system. Xenobiotic receptors, including the aryl hydrocarbon receptor (AHR), sense and respond to a subset of environmental pollutants by activating the expression of detoxification enzymes to protect the body. However, chronic activation of the AHR leads to immunotoxicity. KEAP1–NRF2 is another important system that protects the body against environmental pollutants. KEAP1 is a sensor protein that detects environmental pollutants, leading to activation of the transcription factor NRF2. NRF2 protects the body from immunotoxicity by inducing the expression of genes involved in detoxification, antioxidant and anti-inflammatory activities. Intervening in these sensor–response systems could protect the body from the devastating immunotoxicity that can be induced by environmental pollutants. Exposure to environmental pollutants can lead to immune system dysfunction with severe pathological consequences. Yamamoto and colleagues review the impact of pollutants on immune function and describe potential means to ameliorate these effects.

There are suspected links between air pollution and atopic dermatitis, but the mechanism has remained unclear. Yamamoto and colleagues demonstrate that air pollutants trigger activation of the aryl hydrocarbon receptor in the skin, hyperinnervation and an itch-scratch cycle that leads to atopic dermatitis. 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.

Therapeutic options for treating advanced melanoma are progressing rapidly. Although anti-programmed cell death 1 (PD1) antibodies (e.g., nivolumab, pembrolizumab) have been approved as first-line and anchor drugs, respectively, for treating advanced melanoma, the efficacy appears limited as we expected, especially in Asian populations. Biomarkers to predict or evaluate the efficacy of anti-PD1 antibodies are needed to avoid subjecting patients to potentially severe adverse events associated with switching to other anti-melanoma drugs. This review focuses on the recent development of biomarkers for assessing the efficacy of anti-PD1 antibodies using routine blood tests such as the neutrophil-to-lymphocyte ratio, eosinophil ratio, serum markers such as lactate dehydrogenase, programmed cell death ligand 1 (PD-L1) expression on melanoma cells, microsatellite instability and mismatch repair deficiency assays, as well as soluble CD163, and tumor-associated macrophage-related chemokines (e.g., CXCL5, CXCL10).

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that responds to a wide range of chemicals, including chemical carcinogens such as dioxins and carcinogenic polyaromatic hydrocarbons, and induces a battery of genes associated with detoxification, proliferation, and immune regulation. Recent reports suggest that AHR plays an important role in carcinogenesis and maintenance of various types of skin cancers. Indeed, AHR is a susceptibility gene for squamous cell carcinoma and a prognostic factor for melanoma and Merkel cell carcinoma. In addition, the carcinogenic effects of ultraviolet (UV) and chemical carcinogens, both of which are major environmental carcinogenetic factors of skin, are at least partly mediated by AHR, which regulates UV-induced inflammation and apoptosis, the DNA repair system, and metabolic activation of chemical carcinogens. Furthermore, AHR modulates the efficacy of key therapeutic agents in melanoma. AHR activation induces the expression of resistance genes against the inhibitors of V600E mutated B-Raf proto-oncogene, serine/threonine kinase (BRAF) in melanoma and upregulation of programmed cell death protein 1 (PD-1) in tumor-infiltrating T cells surrounding melanoma. Taken together, these findings underscore the importance of AHR in the biology of skin cancers. Development of therapeutic agents that modulate AHR activity is a promising strategy to advance chemoprevention and chemotherapy for skin cancers.

Aryl hydrocarbon receptor (AhR) provides a deeper insight into the pathogenesis of cutaneous squamous cell carcinoma (cSCC). AhR ligands, such as 6-formylindolo[3,2-b] carbazole (FICZ), and 7,12-Dimethylbenz[a]anthracene (DMBA), constitute major substrates for the cytochrome P450 (CYP) family, and influence the expression of various cytokine genes, including and -related genes via the AhR. On the other hand, proinflammatory cytokines could drive tumor progression through the TRAF-ERK5 signaling pathway in cSCC. From the above findings, we hypothesized that AhR ligands might enhance the mRNA expression of proinflammatory cytokines via the AhR, leading to the development of cSCC. The purpose of this study was to investigate (1) the immunomodulatory effects of FICZ and DMBA on normal human keratinocytes (NHKCs), focusing on IL-17, and related cytokines/chemokines (IL-23, IL-36γ, and CCL20), (2) the expression of these factors in AhR-dependent pathways using a two-stage chemically induced skin carcinogenesis mouse model, and (3) the expression of these factors in lesion-affected skin in cSCC. Both FICZ and DMBA augmented the expression of CYP1A1, p19, CCL20, and IL-36γ mRNA in NHKCs . Moreover, the mRNA expression of these proinflammatory factors, as well as IL-17, in mouse cSCC is significantly decreased in the AhR-(fl/fl) Krt5-(Cre) mice compared to wild type mice, leading to a decrease in the number of developed cSCC lesions. Furthermore, CCL20, IL-23, as well as IL-17, are detected in the lesion-affected skin of cSCC patients. Our study demonstrates a possible mechanism for the development of cSCC involving AhR-mediated signaling by epidermal keratinocytes and recruitment of Th17 cells.

Primary cutaneous apocrine carcinoma (PCAC) is a rare and highly aggressive tumor entity. Since there is no conventional therapy for advanced PCAC, exploratory treatments are sometimes used. As we previously reported, receptor activator of nuclear factor kappa-B (RANK) ligand (RANKL)/RANK signaling on M2 macrophages promotes the production of chemokines and proinflammatory cytokines to maintain the immunosuppressive tumor environment of extramammary Paget's disease (EMPD). Since EMPD is a skin adenocarcinoma of apocrine gland origin that expresses high levels of RANKL and matrix metalloproteinase (MMP) 7, and EMPD is associated with the presence of RANK M2 macrophages, we hypothesized that tumor-associated macrophages (TAMs) in adenocarcinomas such as PCAC might also express RANKL and MMP7. We employed immunohistochemical staining of RANKL and MMP7 in the lesional skin from five patients with PCAC, and microarray analysis of MMPs using human monocyte-derived macrophages. According to DNA microarray analysis, the expression of MMP1 and MMP25 was augmented. The DNA microarray results were verified by using real-time polymerase chain reaction (RT-PCR). Immunohistochemical staining of MMP1 and MMP25 as well as chemokine (C-C motif) ligand (CCL) 5 in the lesional skin from five patients with PCAC showed a substantial number of MMP1-bearing cells and MMP25-bearing cells, as well as CCL5-producing cells, that were distributed in the lesional skin. Our study suggests that the RANKL/RANK pathway contributes to the development and maintenance of the immunosuppressive tumor microenvironment and denosumab may be a promising adjuvant therapy targeting TAMs in cancer of apocrine origin.

Ipilimumab, in combination with nivolumab, is one of the promising drugs that enhance the anti-tumor immune response of patients with advanced melanoma. Since the co-administration of nivolumab with ipilimumab in the neoadjuvant setting expands melanoma-reactive T cells at the primary site of melanoma and has a high rate of histological complete response, the pre-surgical administration of this combination could be the optimal therapy for unresectable advanced melanoma. In this report, a case of unresectable advanced melanoma treated successfully with administration of nivolumab with ipilimumab before primary tumor resection is presented. In addition, CD8+ T cells increased among the tumor-infiltrating lymphocytes that were surrounding melanoma cells and caspase 3+ cells. The present case suggests that pre-surgical administration of nivolumab with ipilimumab could be the optimal therapy for the treatment of unresectable advanced melanoma.

Acquired ichthyosis (AI) is a reactive cutaneous manifestation that can be associated with malignant hematological disease, including cutaneous T-cell lymphoma (CTCL). Since it is difficult to distinguish AI from ichthyosiform mycosis fungoides, to select the treatment for CTCL with ichthyosis-like appearance and to evaluate its efficacy is sometimes challenging. In this report, we describe a case of primary cutaneous peripheral T-cell lymphoma not otherwise specified presenting AI successfully treated with oral bexarotene. In the present case, the administration of oral bexarotene was not only effective for lymphoma cells infiltrating ulcers and nodules, but it also eliminated AI.

Primary cutaneous apocrine carcinoma (PCAC) is a rare and highly aggressive cutaneous adnexal type of tumor that has a high metastasis rate and a poor prognosis. Although there are several case reports describing the successful treatment of PCAC with chemoradiotherapy or molecular targeting therapy, no standard therapy for the treatment of advanced PCAC has been established yet. Since receptor activator of nuclear factor kappa-B ligand (RANKL) is expressed in cancers of apocrine origin, leading to immunosuppression at the tumor site, we hypothesized that targeting RANKL with denosumab might be useful for the treatment of PCAC. In this report, we describe a case with advanced PCAC on the scrotum successfully treated with systemic chemotherapy using carboplatin and paclitaxel, and radiotherapy followed by denosumab.

Both long-term administration of immunosuppressive agents and chronic inflammatory conditions, such as autoimmune disease, could be risk factors for the development of cutaneous squamous cell carcinoma (cSCC). In this report, we present a case of recurrent multiple cSCC on the scalp in a patient with juvenile dermatomyositis who had been administered cyclosporine and Predonine since she was a 1-year-old infant. Interestingly, immunohistochemical staining revealed IL-17-producing cells adjacent to IL-17R-expressing atypical keratinocytes. Our present case suggested that IL-17/IL-17R signaling might contribute to the carcinogenesis of cSCC.