RESUMO
BACKGROUND: Sensory nerves regulate cutaneous local inflammation indirectly through induction of pruritus and directly by acting on local immune cells. The underlying mechanisms for how sensory nerves influence cutaneous acquired immune responses remain to be clarified. OBJECTIVE: This study aimed to explore the effect of peripheral nerves on cutaneous immune cells in cutaneous acquired immune responses. METHODS: We analyzed contact hypersensitivity (CHS) responses as a murine model of delayed-type hypersensitivity in absence or presence of resiniferatoxin-induced sensory nerve denervation. We conducted ear thickness measurements, flow cytometric analyses, and mRNA expression analyses in CHS. RESULTS: CHS responses were attenuated in mice that were denervated during the sensitization phase of CHS. By screening neuropeptides, we found that pituitary adenylate cyclase-activating polypeptide (PACAP) mRNA expression was decreased in the dorsal root ganglia after denervation. Administration of PACAP restored attenuated CHS response in resiniferatoxin-treated mice, and pharmacological inhibition of PACAP suppressed CHS. Flow cytometric analysis of skin-draining lymph nodes showed that cutaneous dendritic cell migration and maturation were reduced in both denervated mice and PACAP antagonist-treated mice. The expression of chemokine receptors CCR7 and CXCR4 of dendritic cell s was enhanced by addition of PACAP in vitro. CONCLUSION: These findings indicate that a neuropeptide PACAP promotes the development of CHS responses by inducing cutaneous dendritic cell functions during the sensitization phase.
Assuntos
Dermatite de Contato/imunologia , Células de Langerhans/imunologia , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/imunologia , Animais , Denervação , Dermatite de Contato/genética , Diterpenos/administração & dosagem , Feminino , Gânglios Espinais/fisiologia , Haptenos/administração & dosagem , Linfonodos/imunologia , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Neurotoxinas/administração & dosagem , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética , Receptores CCR7/imunologia , Receptores CXCR4/imunologia , Canais de Cátion TRPVRESUMO
Anti-programmed cell death protein 1 (PD1) antibodies are in wide use for the treatment of various cancers. PD1 antibody-based immunotherapy, co-administration of nivolumab and ipilimumab, is one of the optimal immunotherapies, especially in advanced melanoma with high tumor mutation burden. Since this combined therapy leads to a high frequency of serious immune-related adverse events (irAEs) in patients with advanced melanoma, biomarkers are needed to evaluate nivolumab efficacy to avoid serious irAEs caused by ipilimumab. This study analyzed baseline serum levels of CXCL5, CXCL10, and CCL22 in 46 cases of advanced cutaneous melanoma treated with nivolumab. Baseline serum levels of CXCL5 were significantly higher in responders than in non-responders. In contrast, there were no significant differences in baseline serum levels of CXCL10 and CCL22 between responders and non-responders. These results suggest that baseline serum levels of CXCL5 may be useful as a biomarker for identifying patients with advanced cutaneous melanoma most likely to benefit from anti-melanoma immunotherapy.
RESUMO
BACKGROUND: The objective of this study was to identify predictive markers, including inflammatory and nutritional status measures, of early progressive disease (EPD) in unresectable melanoma patients treated with nivolumab. METHODS: A retrospective review was performed on 39 consecutive patients with unresectable melanoma treated with nivolumab. EPD was defined as progressive disease within 60 days after starting nivolumab according to Response Evaluation Criteria in Solid Tumors version 1.1. The predictive index model [melanoma inflammation index (MII)] was determined by the number of predictive factors. RESULTS: Seventeen patients had cutaneous melanoma and 22 patients had mucosal melanoma. The overall response rate was 18.4%, and the response rates for cutaneous and mucosal melanoma were 29.4% and 9.5%, respectively. EPD was observed in 13 patients (34.2%). By multivariate analysis, body mass index (BMI) and C-reactive protein to albumin ratio (CAR) were independently and significantly associated with EPD, disease control rate, progression-free survival, and overall survival. Low BMI (cutoff 20) and high CAR (cutoff 0.0055) were predictive factors of EPD and were determined to be prognostic factors. MII, from 0 to 2, was determined by the number of these factors. The incidence of EPD was 0% in the low-risk group (MII = 0), 50% in the intermediate-risk group (MII = 1), and 83% in the high-risk group (MII = 2). CONCLUSIONS: An MII status of low BMI and high CAR may be used to predict EPD in unresectable melanoma patients treated with nivolumab.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Melanoma/tratamento farmacológico , Nivolumabe/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Índice de Massa Corporal , Proteína C-Reativa/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Melanoma/mortalidade , Melanoma/cirurgia , Pessoa de Meia-Idade , Estado Nutricional , Estudos Retrospectivos , Fatores de Risco , Albumina Sérica Humana/metabolismo , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/cirurgia , Resultado do Tratamento , Melanoma Maligno CutâneoAssuntos
Antineoplásicos Imunológicos/efeitos adversos , Melanoma/tratamento farmacológico , Nivolumabe/efeitos adversos , Esclerodermia Localizada/imunologia , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Biópsia , Dedos , Humanos , Masculino , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Esclerodermia Localizada/diagnóstico , Esclerodermia Localizada/patologia , Pele/imunologia , Pele/patologia , SíndromeRESUMO
Antibodies against programmed cell death protein 1, such as nivolumab and pembrolizumab, are widely used for treating various cancers, including advanced melanoma. Nivolumab significantly prolongs survival in patients with metastatic melanoma, and sequential administration with lipilimumab may improve outcomes when switched at the appropriate time. Biomarkers are therefore needed to evaluate nivolumab efficacy soon after first administration. This study analyzed serum levels of soluble cluster of differentiation 163 (sCD163) in 59 cases of advanced cutaneous melanoma and 16 cases of advanced mucosal melanoma treated using nivolumab. Serum levels of sCD163 were significantly increased after 6 weeks in responders compared to non-responders after initial administration of nivolumab for cutaneous melanoma. In contrast, no significant difference between responders and non-responders was seen among patients with non-cutaneous melanoma. These results suggest that sCD163 may be useful as a biomarker for selecting patients with advanced cutaneous melanoma most likely to benefit from anti-melanoma immunotherapy.
RESUMO
Antibodies against PD-1, such as nivolumab and pembrolizumab, are widely used in the treatment of various cancers including advanced melanoma. The anti-PD-1 Ab significantly prolongs survival in patients with metastatic melanoma, and its administration in combination with local or systemic therapy may also lead to improved outcomes. Although anti-PD-1 Ab-based combined therapy might be effective for the treatment of advanced melanoma, the associated risk of irAEs is an important consideration. Therefore, being able to predict irAEs is of great interest to oncologists. The purpose of this study was to evaluate the value of using serum levels of sCD163 and CXCL5 to predict irAEs in patients with advanced melanoma who were administered nivolumab. To this end, we analyzed these serum levels in 46 cases of advanced melanoma treated with nivolumab. In addition, the tumor stroma was evaluated by immunohistochemistry and immunofluorescence. We measured the serum levels of sCD163 and CXCL5 on day 0 (immediately before nivolumab administration) and day 42. The serum absolute levels of sCD163 were significantly increased in patients who developed AEs (p = 0.0018). Although there was no significant difference in serum levels of CXCL5, the absolute value of CXCL5 could at least be a supportive marker for the increased absolute levels of serum sCD163. This study suggests that sCD163 and CXCL5 may serve as possible prognostic biomarkers for irAEs in patients with advanced melanoma treated with nivolumab.
RESUMO
BACKGROUND: The objective of this study was to evaluate the efficacy and safety of concurrent immune checkpoint inhibitor therapy and radiotherapy (immunoradiotherapy) in patients with metastatic melanoma after progression on nivolumab. PATIENTS AND METHODS: A retrospective review was performed on 16 consecutive patients with metastatic melanoma treated with concurrent immunoradiotherapy after progression on nivolumab. Best responses to immunoradiotherapy were assessed either inside or outside of the radiation fields. The target lesions ratio (the sum of the diameters of the target lesions inside the irradiated fields/all target lesions) was also assessed. RESULTS: Among the patients, seven received ipilimumab and radiotherapy (Ipi-RT), six received nivolumab and radiotherapy (Nivo-RT), and three sequentially received Ipi-RT and Nivo-RT. The overall response rate (all patients regardless of inside or outside radiation fields) was 30%. The response rate inside the radiation fields was 68.8% for all patients combined. The response rates of Ipi-RT and Nivo-RT inside the radiation fields were 37.5 and 100% (P = 0.03), respectively. Grade 3 adverse events were observed in three patients treated with Ipi-RT. The target lesions ratio was a predictive marker of disease control rate among patients treated with Nivo-RT. CONCLUSIONS: This study showed that concurrent immunoradiotherapy is an option for patients with metastatic melanoma after progression on nivolumab.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Quimiorradioterapia/métodos , Melanoma/terapia , Neoplasias Cutâneas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/farmacologia , Quimiorradioterapia/efeitos adversos , Receptores Coestimuladores e Inibidores de Linfócitos T/antagonistas & inibidores , Receptores Coestimuladores e Inibidores de Linfócitos T/imunologia , Progressão da Doença , Feminino , Humanos , Ipilimumab/farmacologia , Ipilimumab/uso terapêutico , Masculino , Melanoma/imunologia , Melanoma/patologia , Pessoa de Meia-Idade , Nivolumabe/farmacologia , Nivolumabe/uso terapêutico , Estudos Retrospectivos , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Resultado do TratamentoRESUMO
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.
Assuntos
Anafilaxia/imunologia , Asma/imunologia , Basófilos/fisiologia , Inflamação/imunologia , Mastócitos/fisiologia , Amina Oxidase (contendo Cobre)/metabolismo , Animais , Biomarcadores/metabolismo , Degranulação Celular , Humanos , Mediadores da Inflamação/metabolismo , Lipídeos/imunologia , Diester Fosfórico Hidrolases/metabolismo , Pirofosfatases/metabolismo , Tetraspanina 30/metabolismoAssuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos Imunológicos/efeitos adversos , Toxidermias/etiologia , Líquen Nítido/induzido quimicamente , Neoplasias Pulmonares/tratamento farmacológico , Nivolumabe/efeitos adversos , Adenocarcinoma/secundário , Adulto , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Nivolumab is a monoclonal antibody directed against programmed death-1 that has been shown to improve survival in patients with metastatic melanoma. However, the efficacy of nivolumab and other agents in melanoma remains limited. The objective of this study was to evaluate the efficacy and safety of retreatment with nivolumab in metastatic melanoma patients who previously progressed on nivolumab. PATIENTS AND METHODS: A retrospective review was performed on eight consecutive metastatic melanoma patients retreated with nivolumab who progressed on previous nivolumab. These patients received nivolumab 2 mg/kg every 3 weeks. Best responses to each treatment were assessed using RECIST 1.1. RESULTS: Of eight metastatic melanoma patients, three patients received chemotherapy before first nivolumab. The median first nivolumab treatment period was 4.1 months. During first nivolumab, 3 (37.5%) patients achieved a partial response and 3 (37.5%) patients achieved stable disease as their best response. First nivolumab was discontinued due to disease progression in seven patients and grade 3 colitis in 1 patient. Patients were subsequently treated with ipilimumab (n = 6), vemurafenib (n = 1), or no other medical treatment (n = 1). The median treatment period between first and second nivolumab was 3.0 months. Four patients received radiation therapy between first and second nivolumab. The median second nivolumab treatment period was 4.3 months. Among the eight patients who received second nivolumab, 2 (25%) patients achieved a partial response and 3 (37.5%) patients achieved stable disease as their best response. Second nivolumab was discontinued due to disease progression in seven patients. One patient continues to receive second nivolumab. Among the four patients treated with ipilimumab and radiotherapy between first and second nivolumab, the response rate was 50% and the disease control rate was 75%. CONCLUSIONS: This study showed that retreatment with nivolumab is an option for select metastatic melanoma patients after previous nivolumab treatment.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Melanoma/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nivolumabe , Estudos RetrospectivosRESUMO
BACKGROUND: Although nivolumab significantly prolongs survival of metastatic melanoma, about 10% of patients experience severe, even fatal immune-related adverse events (irAEs). Biomarkers to predict irAEs are, therefore, of great interest. OBJECTIVE: We aimed to correlate changes in routine blood count parameters to the occurrence of serious irAEs (grade 3/4 [G3/4] or lung/gastrointestinal [lung/GI] irAEs) in patients with melanoma who were treated with nivolumab. METHODS: We retrospectively analyzed data from 101 patient with melanoma treated with nivolumab from 8 institutes in Japan. We used logistic regression analyses to investigate associations between severe irAEs and fluctuations in routine blood count parameters (total white blood cell [WBC] count, relative neutrophil, monocyte, lymphocyte, and eosinophil count) during the treatment. Receiver-operating characteristic curve was used to determine a cutoff value for the blood count parameters and area under the curve (AUC). RESULTS: Univariate analysis revealed that G3/4 irAEs were associated with increased total WBC count (P=0.034, cutoff value=+27%, AUC=0.68, odds ratio [OR]=1.58) and decreased relative lymphocyte count (RLC, P=0.042, cutoff value=-23%, AUC=0.65, OR=1.65). However, multivariate analysis showed that the same factors, increased WBC count (P=0.014, cutoff value=+59.1%, AUC=0.79, OR=6.04) and decreased RLC (P=0.012, cutoff value=-32.3%, AUC=0.81, OR=5.01) were independent factors associated with lung/GI irAEs. CONCLUSIONS: Our results suggest that increased WBC count and decreased RLC are associated with G3/4 and lung/GI irAEs. Our analysis was based on the data point at which irAE occurrence was noticed and, therefore, these factors are not predictive, however, they could be a "signal" of severe irAE occurrence in patients with melanoma treated with nivolumab.
Assuntos
Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Sistema Imunitário/efeitos dos fármacos , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Análise Custo-Benefício , Monitoramento de Medicamentos/economia , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Japão , Contagem de Leucócitos/economia , Contagem de Leucócitos/métodos , Masculino , Melanoma/sangue , Pessoa de Meia-Idade , Nivolumabe , Curva ROC , Estudos Retrospectivos , Sensibilidade e Especificidade , Neoplasias Cutâneas/sangueRESUMO
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.
Assuntos
Macrófagos/metabolismo , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Hipóxia Tumoral , Animais , Proliferação de Células , Feminino , Proteína HMGB1/sangue , Proteína HMGB1/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Interleucina-10/metabolismo , Macrófagos/patologia , Masculino , Melanoma Experimental/sangue , Camundongos Endogâmicos C57BL , Fenótipo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologiaAssuntos
Dermatite Atópica/metabolismo , Dermatite Atópica/fisiopatologia , Epiderme/inervação , Prurido/metabolismo , Prurido/fisiopatologia , Psoríase/metabolismo , Psoríase/fisiopatologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Aminoquinolinas/toxicidade , Animais , Axitinibe , Dermatite Atópica/patologia , Modelos Animais de Doenças , Humanos , Imidazóis/farmacologia , Imiquimode , Indazóis/farmacologia , Camundongos , Prurido/tratamento farmacológico , Prurido/patologia , Psoríase/patologia , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidoresAssuntos
Basófilos/imunologia , Dermatite Esfoliativa/imunologia , Dermatopatias Vesiculobolhosas/imunologia , Pele/imunologia , Administração Cutânea , Corticosteroides/administração & dosagem , Idoso , Basófilos/efeitos dos fármacos , Basófilos/patologia , Basófilos/efeitos da radiação , Biomarcadores/análise , Biópsia , Terapia Combinada , Dermatite Esfoliativa/patologia , Dermatite Esfoliativa/terapia , Humanos , Imuno-Histoquímica , Masculino , Prurido/imunologia , Prurido/terapia , Pele/efeitos dos fármacos , Pele/patologia , Pele/efeitos da radiação , Dermatopatias Vesiculobolhosas/patologia , Dermatopatias Vesiculobolhosas/terapia , Resultado do Tratamento , Terapia Ultravioleta , Regulação para CimaRESUMO
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-ß) 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-ß compared to non-responders. Th9 induction by IL-4 and TGF-ß 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.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Neoplasias Cardíacas/imunologia , Linfócitos do Interstício Tumoral/imunologia , Micose Fungoide/imunologia , Neoplasias Cutâneas/imunologia , Adulto , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/análise , Biópsia , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Neoplasias Cardíacas/secundário , Neoplasias Cardíacas/terapia , Humanos , Imuno-Histoquímica , Imunofenotipagem , Metástase Linfática , Masculino , Micose Fungoide/sangue , Micose Fungoide/patologia , Micose Fungoide/terapia , Estadiamento de Neoplasias , Fenótipo , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapiaRESUMO
Extramammary Paget's disease is a rare cutaneous malignant neoplasm. Previous studies indicated the efficacy of docetaxel in advanced cases. The common side effects of docetaxel are usually tolerable and seldom life-threatening. We experienced a case of severe pseudomembranous colitis and neutropenic fever that developed just after the first cycle of docetaxel chemotherapy. To the best of our knowledge, there are few reports of pseudomembranous colitis associated with docetaxel administration for skin cancers. The patient showed complete resolution of her symptoms within 2 weeks with an oral metronidazole therapy. During the second and third cycles, the patient received docetaxel safely with lower doses. The present case indicated that pseudomembranous colitis should be included in the differential diagnosis when assessing patients who develop severe diarrhea during systemic chemotherapy with docetaxel.