He had been treated for acral lentiginous melanoma and had undergone excision of the tumors and left inguinal lymph node dissection (pT4aN3cM0 stage IIIC). melanoma patients [1, 2]. On the other hand, the efficacy of ipilimumab in nivolumab-resistant advanced melanoma is only 3.6% [3], suggesting that additional supportive therapy for anti-PD-1 antibody is needed for nivolumab-resistant advanced melanoma. Indeed, although several supportive therapies to enhance the antitumor immune response of anti-PD-1 antibodies have already been reported [3, 4, 5, 6, 7, 8], unexpected immune-related adverse events were detected at the same time [8]. In this report, we describe a patient with advanced melanoma treated with nivolumab followed by intensity-modulated radiotherapy (IMRT), which might have brought on bullous pemphigoid (BP). Case Reports (-)-Epicatechin gallate A 77-year-old Japanese man frequented our outpatient clinic with a slight pain around the neck. He had been treated for acral lentiginous (-)-Epicatechin gallate melanoma and had undergone excision of the tumors WDFY2 and left inguinal lymph node dissection (pT4aN3cM0 stage IIIC). In addition, after the surgical treatment, he had received adjuvant chemotherapy (dacarbazine with interferon-, 3.0 106 U) for a half 12 months. We screened for possible metastatic lesions with positron emission tomography and found an 11 mm nodule at the second cervical vertebra (Fig. ?(Fig.1a).1a). Since the primary tumor was unfavorable for the BRAFV600E mutation, we administered nivolumab at 2 mg/kg q3 weeks. (-)-Epicatechin gallate Since a follow-up computed tomography scan 9 weeks after the administration of nivolumab revealed progression of the nodule at the second cervical vertebra, we employed IMRT (45 Gy in 5 fractions) 10 weeks after the administration of nivolumab. Seven weeks after the IMRT irradiation, the patient developed large, tense bullae and erosion arising on erythematous plaque around the trunk and extremities (Fig. ?(Fig.1b).1b). A biopsy specimen revealed prominent interface dermatitis and dense infiltration of eosinophils in the upper dermis (Fig. ?(Fig.1c).1c). Direct immunofluorescent study revealed IgG deposition around the epidermal side of the basement membrane zone. High levels of serum anti-BP180 NC16a antibody (73.1 U/mL) were detected. From the above findings, we made the diagnosis of BP developing in a patient with advanced (-)-Epicatechin gallate melanoma treated with nivolumab and IMRT. We treated him with oral prednisolone 20 mg/day with doxycycline (100 mg/day) with nivolumab. Two weeks later, the initial eruptions had disappeared and his disease was under control. Open in a separate windows Fig. 1 a Positron emission tomography revealed an 11 mm nodule at the second cervical vertebra. b Large, tense bullae and erosion arising on erythematous plaque around the trunk and extremities. c A prominent interface dermatitis and dense infiltration of eosinophils in the upper dermis. H&E staining. Original magnification 100. Discussion Since the efficacy rate of nivolumab monotherapy for advanced melanoma is usually approximately 30% [1], enhancing the antitumor immune response induced by nivolumab is necessary to further optimize its use for the treatment of advanced melanoma [2]. Indeed, several successful methods to enhance the antitumor effects of nivolumab by local or systemic therapies have already been created [1, 2, 3, 4, 5, 6, 9]. Alternatively, these combination treatments develop unexpected, serious immune-related adverse occasions [1, 2, 3]. With this record, we describe a complete case of BP in an individual with advanced melanoma treated with nivolumab, caused by IMRT probably. BP can be an autoimmune blistering disease affecting older people predominantly. Recent reports possess suggested that many immune cells such as for example regulatory T cells (Tregs), T helper 17 (Th17), and skin-resident M2-like macrophages donate to the pathogenesis of BP [10, 11, 12, 13]. Certainly, the amount of Tregs can be significantly reduced in the lesional pores and skin of BP individuals compared with additional inflammatory pores and skin diseases such as for example atopic dermatitis [10]. Furthermore, Furudate et al. [12] reported a substantial amount of M2 macrophages in the lesional BP pores and skin, resulting in the recruitment of immune system cells in the lesional BP pores and skin [11]. These reviews suggested a feasible part of M2 macrophages in the pathogenesis of BP [11]. Oddly enough, Gordon et al. [14] reported the manifestation of PD-1 on M2-like tumor-associated macrophages (TAMs) in colorectal malignancies in human beings and mice, resulting in suppressed antitumor features of M2-like TAMs by PD-1/ PD-L1-reliant pathways. Furthermore, Rannou et al. [15] reported that radiotherapy raises M1-polarized macrophages in tumor-bearing hosts. Notably, the primary human population of TAMs can be M2-polarized macrophages and one of many features of TAMs in tumor microenvironment can be to (-)-Epicatechin gallate produce different chemokines that recruit Tregs, aswell as communicate immunosuppressive molecules such as for example PD-L1 [16, 17]. In aggregate, the obstructing of PD-1/PD-L1 by nivolumab with IMRT may cause TAMs to abrogate their immunosuppressive function, resulting in the introduction of.