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1.
Artigo em Inglês | MEDLINE | ID: mdl-34268602

RESUMO

Cancer cells are able to escape immune surveillance by upregulating programmed death ligand 1 (PD-L1). A key regulator of PD-L1 expression is transcriptional stimulation by the IFNγ/JAK/STAT pathway. Recent studies suggest that hypoxia can induce PD-L1 expression. As hypoxia presents a hallmark of solid tumor development, hypoxic control of PD-L1 expression may affect the efficacy of cancer immunotherapy. This study aims to explore the hypoxic regulation of PD-L1 expression in human melanoma, and its interaction with IFNγ-induced PD-L1 expression. Analysis of the cutaneous melanoma dataset from the cancer genome atlas revealed a significant correlation of the HIF1-signaling geneset signature with PD-L1 mRNA expression. However, this correlation is less pronounced than other key pathways known to control PD-L1 expression, including the IFNγ/JAK/STAT pathway. This secondary role of HIF1 in PD-L1 regulation was confirmed by analyzing single-cell RNA-sequencing data of 33 human melanoma tissues. Interestingly, PD-L1 expression in these melanoma tissues was primarily found in macrophages. However, also in these cells STAT1, and not HIF1, displayed the most pronounced correlation with PD-L1 expression. Moreover, we observed that hypoxia differentially affects PD-L1 expression in human melanoma cell lines. Knockdown of HIF1 expression indicated a minor role for HIF1 in regulating PD-L1 expression. A more pronounced influence of hypoxia was found on IFNγ-induced PD-L1 mRNA expression, which is controlled at a 952 bp PD-L1 promoter fragment. These findings, showing the influence of hypoxia on IFNγ-induced PD-L1 expression, are relevant for immunotherapy, as both IFNγ and hypoxia are frequently present in the tumor microenvironment.

2.
Exp Dermatol ; 30(9): 1254-1257, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34081788

RESUMO

The SARS-CoV-2 pandemic has evolved to a global health problem with a dramatic morbidity and mortality rate impacting our daily life and those of many patients. While there is evidence that some diseases are associated with an increased risk for development of a more severe course of COVID-19, little is known on protective conditions. Importantly, clearance of viral infection and protection against disease manifestation crucially depends on functional innate and adaptive immunity and the interferon signalling axis. Here, we hypothesize that patients with non-segmental vitiligo (NSV), an autoimmune skin (and mucosal) disorder, may clear SARS-CoV-2 infection more efficiently and have a lower risk of COVID-19 development. Conversely, in case of COVID-19 development, vitiligo autoimmunity may influence the cytokine storm-related disease burden. In addition, immune activation during SARS-CoV-2 infection or COVID-19 disease might increase vitiligo disease activity. Our hypothesis is based on the shift of the immune system in NSV towards adaptive type 1 (IFNγ and CD8 T cells) and innate immune responses. Identified susceptibility genes of NSV patients may further confer increased antiviral activity. To validate our hypothesis, we suggest an international consortium to perform a retrospective data registry and patient-reported study on a large number of NSV patients worldwide during the COVID-19 pandemic.


Assuntos
Doenças Autoimunes/epidemiologia , COVID-19/epidemiologia , Vitiligo/epidemiologia , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , COVID-19/complicações , COVID-19/imunologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/virologia , Predisposição Genética para Doença , Humanos , Imunidade Inata , Fatores de Proteção , SARS-CoV-2 , Vitiligo/genética , Vitiligo/imunologia
3.
J Invest Dermatol ; 2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34166674

RESUMO

Accumulating studies have indicated immune-based destruction of melanocytes in both segmental vitiligo (SV) and non-SV (NSV). Whereas SV often occurs unilaterally during childhood and stabilizes after an initial period of activity, the disease course of NSV is usually slowly progressive, with new lesions occurring bilaterally during life. This suggests an involvement of distinct pathophysiology pathways, specifically increased systemic immune activation in patients with NSV but not in patients with SV. This research aimed to identify the differences in immune cells in the blood of patients with SV and NSV through immunophenotyping of circulating cells. Regulatory T cells were unaffected in patients with SV compared with that in healthy controls but decreased in patients with NSV. In patients with NSV, the reduction in regulatory T cells was associated with the presence of other systemic autoimmune comorbidities, which were less present in SV. Similarly, the absence of a melanocyte-specific antibody response in patients with SV suggests less involvement of B-cell immunity in SV. These data show that in contrast to patients with NSV, no increased systemic immunity is found in patients with SV, indicating that SV pathogenesis is associated with a localized cytotoxic reaction targeting epidermal melanocytes.

4.
J Histochem Cytochem ; 69(5): 339-346, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33797290

RESUMO

The Opal multiplex technique is an established methodology for the detection of multiple biomarkers in one section. The protocol encompasses iterative single stainings and heating-mediated removal of the primary and secondary antibodies after each staining round, leaving untouched the Opal fluorophores which are deposited onto the antigen of interest. According to our experience, repetitive heating of skin sections often results in tissue damage, indicating an urgent need for milder alternatives to strip immunoglobulins. In this study, we demonstrate that considerable heating-related damage was found not only in skin but also in tissues of different origin, mostly characterized by low cell density. Importantly, the morphology remained fully intact when sections were repetitively exposed to ß-mercaptoethanol-containing stripping buffer instead of multiple heating cycles. However, target epitopes appeared sensitive at a differential degree to multiple treatments with stripping buffer, as shown by loss in staining intensity, but in all cases, the staining intensity could be restored by increment of the primary antibody concentrations. Application of ß-mercaptoethanol-containing stripping buffer instead of heating for antibody removal markedly improved the quality of the Opal multiplex technique, as a substantial higher number of differently colored cells could be visualized within a well-conserved morphological context.


Assuntos
Imunofluorescência/métodos , Fluxo de Trabalho , Corantes Fluorescentes/metabolismo , Humanos , Imuno-Histoquímica , Coloração e Rotulagem
5.
Expert Opin Drug Saf ; 20(8): 883-888, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33896329

RESUMO

Introduction: Treatment with immune checkpoint inhibitors in melanoma patients can cause immune-related adverse effects, such as vitiligo. In vitiligo, specific autoimmunity against melanocytes results in depigmentation of the skin. Melanoma-associated vitiligo occurring in melanoma patients treated with immune checkpoint inhibitors can be seen as a good prognostic sign as higher survival rates in melanoma-associated vitiligo cases have been reported.Areas covered: This review gives an insight into the pathophysiology, clinical presentation, and management of melanoma-associated vitiligo caused by immune checkpoint inhibitors.Expert opinion: Development of melanoma-associated vitiligo induced by immune checkpoint inhibitors could be a good clinical marker for response and overall survival. Induction of vitiligo in these patients could also potentially lead to better response and survival rates. Further research should focus on several aspects of melanoma-associated vitiligo, such as better screening and registration, more understanding of pathophysiology of the type of immune response and the predictive value of melanoma-associated in patients treated with immune checkpoint inhibitors.


Assuntos
Inibidores de Checkpoint Imunológico/efeitos adversos , Vitiligo/induzido quimicamente , Vitiligo/tratamento farmacológico , Animais , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Melanoma/tratamento farmacológico , Valor Preditivo dos Testes , Prognóstico , Neoplasias Cutâneas/tratamento farmacológico , Taxa de Sobrevida , Resultado do Tratamento , Vitiligo/fisiopatologia
6.
Nat Protoc ; 16(2): 791-811, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33349704

RESUMO

Human skin harbors various immune cells that are crucial for the control of injury and infection. However, the current understanding of immune cell function within viable human skin tissue is limited. We developed an ex vivo imaging approach in which fresh skin biopsies are mounted and then labeled with nanobodies or antibodies against cell surface markers on tissue-resident memory CD8+ T cells, other immune cells of interest, or extracellular tissue components. Subsequent longitudinal imaging allows one to describe the dynamic behavior of human skin-resident cells in situ. In addition, this strategy can be used to study immune cell function in murine skin. The ability to follow the spatiotemporal behavior of CD8+ T cells and other immune cells in skin, including their response to immune stimuli, provides a platform to investigate physiological immune cell behavior and immune cell behavior in skin diseases. The mounting, staining and imaging of skin samples requires ~1.5 d, and subsequent tracking analysis requires a minimum of 1 d. The optional production of fluorescently labeled nanobodies takes ~5 d.


Assuntos
Pele/imunologia , Pele/patologia , Coloração e Rotulagem/métodos , Animais , Biópsia/métodos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Técnicas de Cultura de Células/métodos , Humanos , Camundongos , Pele/citologia
7.
Front Immunol ; 11: 579022, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33240267

RESUMO

Autoreactive CD8+ T cells play a pivotal role in melanocyte destruction in autoimmune vitiligo. Immunotherapy for melanoma often leads to autoimmune side-effects, among which vitiligo-like depigmentation, indicating that targeting immune checkpoints can break peripheral tolerance against self-antigens in the skin. Therapeutically enhancing immune checkpoint signaling by immune cells or skin cells, making self-reactive T cells anergic, seems a promising therapeutic option for vitiligo. Here, we review the current knowledge on the PD-1/PD-L1 pathway in vitiligo as new therapeutic target for vitiligo therapy.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Linfócitos T CD8-Positivos/efeitos dos fármacos , Inibidores de Checkpoint Imunológico/uso terapêutico , Melanócitos/efeitos dos fármacos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Pigmentação da Pele/efeitos dos fármacos , Pele/efeitos dos fármacos , Vitiligo/tratamento farmacológico , Animais , Autoimunidade/efeitos dos fármacos , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Humanos , Melanócitos/imunologia , Melanócitos/metabolismo , Terapia de Alvo Molecular , Receptor de Morte Celular Programada 1/metabolismo , Transdução de Sinais , Pele/imunologia , Pele/metabolismo , Pele/fisiopatologia , Vitiligo/imunologia , Vitiligo/metabolismo , Vitiligo/fisiopatologia
8.
Am J Dermatopathol ; 42(8): 625-627, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32701706

RESUMO

The cancer/testis antigens (CTA) are a group of antigens expressed on germ cells of healthy testis and malignant tumors. We studied whether CTA are present on lentigo maligna (LM) and LM melanoma (LMM) samples. Immunohistochemical expression of a panel of CTA (MAGE-A1, A2- A3, NY-ESO-1, PRAME, SSX-2, and a MAGE-A antibody reactive with -A1, -A2, -A3, -A4, -A6, -A10, and -A12) was investigated in formalin-fixed paraffin-embedded samples from LMM (n = 20), LM (n = 8), chronically sun-exposed skin (n = 7), and healthy skin (n = 7). In 4 LMM lesions, the MAGE-A marker was positive. Another 3 LMM lesions were positive for MAGE-A1, MAGE-A2, and MAGE-A3. PRAME was positive in 18/20 LMM and 6/8 LM. We did not find expression of MAGE, NY-ESO-1, or SSX-2 in LM, thereby excluding these CTA as diagnostic markers to discern malignant melanocytes in LM from normal melanocytes. LMM did express MAGE, NY-ESO-1, and SSX-2. If a biopsy from a lesion suspect for LM shows positivity for MAGE, NY-ESO-1, and SSX-2, the lesion may actually be LMM. In contrast, PRAME expression was found in LM at low levels and in LMM at much higher levels, and absent in normal melanocytes. PRAME can potentially be used to discern normal melanocytes from malignant melanocytes.


Assuntos
Antígenos de Neoplasias/biossíntese , Biomarcadores/análise , Carcinoma in Situ/diagnóstico , Sarda Melanótica de Hutchinson/diagnóstico , Neoplasias Cutâneas/diagnóstico , Carcinoma in Situ/metabolismo , Carcinoma in Situ/patologia , Humanos , Sarda Melanótica de Hutchinson/metabolismo , Sarda Melanótica de Hutchinson/patologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia
10.
Nat Immunol ; 21(6): 696, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32210390

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

11.
Pigment Cell Melanoma Res ; 32(5): 612-622, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31230406

RESUMO

Tissue-resident memory T (TRM ) cells are abundant in the memory T cell pool and remain resident in peripheral tissues, such as the skin, where they act as alarm sensors or cytotoxic killers. TRM cells persist long after the pathogen is eliminated and can respond rapidly upon reinfection with the same antigen. When aberrantly activated, skin-located TRM cells have a profound role in various skin disorders, including vitiligo and melanoma. Autoreactive TRM cells are present in human lesional vitiligo skin and mouse models of vitiligo, which suggests that targeting these cells could be effective as a durable treatment strategy for vitiligo. Furthermore, emerging evidence indicates that induction of melanoma-reactive TRM cells is needed to achieve effective protection against tumor growth. This review highlights seminal reports about skin-resident T cells, focusing mainly on their role in the context of vitiligo and melanoma, as well as their potential as therapeutic targets in both diseases.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/imunologia , Melanoma/terapia , Pele/imunologia , Vitiligo/terapia , Animais , Linfócitos T CD8-Positivos/patologia , Humanos , Ativação Linfocitária , Melanoma/imunologia , Melanoma/patologia , Pele/patologia , Vitiligo/imunologia , Vitiligo/patologia
12.
Nat Immunol ; 20(6): 756-764, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31110315

RESUMO

Emerging data show that tissue-resident memory T (TRM) cells play an important protective role at murine and human barrier sites. TRM cells in the epidermis of mouse skin patrol their surroundings and rapidly respond when antigens are encountered. However, whether a similar migratory behavior is performed by human TRM cells is unclear, as technology to longitudinally follow them in situ has been lacking. To address this issue, we developed an ex vivo culture system to label and track T cells in fresh skin samples. We validated this system by comparing in vivo and ex vivo properties of murine TRM cells. Using nanobody labeling, we subsequently demonstrated in human ex vivo skin that CD8+ TRM cells migrated through the papillary dermis and the epidermis, below sessile Langerhans cells. Collectively, this work allows the dynamic study of resident immune cells in human skin and provides evidence of tissue patrol by human CD8+ TRM cells.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Memória Imunológica , Pele/imunologia , Animais , Antígenos/imunologia , Linhagem Celular Tumoral , Movimento Celular/imunologia , Epiderme/imunologia , Epiderme/metabolismo , Imunofluorescência , Humanos , Camundongos , Especificidade de Órgãos/imunologia , Anticorpos de Domínio Único/imunologia , Pele/metabolismo , Vacinas de DNA/genética , Vacinas de DNA/imunologia
13.
Melanoma Res ; 29(5): 453-464, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30855527

RESUMO

Immune checkpoint inhibitors (ICIs), which target CTLA-4 or PD-(L)1 molecules, have shown impressive therapeutic results. Durable responses, however, are only observed in a segment of the patient population and must be offset against severe off-target immune toxicity and high costs. This calls for biomarkers that predict response during ICI treatment. Although many candidate biomarkers exist, as yet, there has been no systematic overview of biomarkers predictive during. Here, we provide a systematic review of the current literature of ICI treatment to establish an overview of candidate predictive biomarkers during ICI treatment in melanoma patients. We performed a systematic Medline search (2000-2018, 1 January) on biomarkers for survival or response to ICI treatment in melanoma patients. We retrieved 735 publications, of which 79 were finally included in this systematic review. Blood markers were largely studied for CTLA-4 ICI, whereas tumor tissue markers were analyzed for PD-(L)1 ICI. Blood cytology and soluble factors were more frequently correlated to overall survival (OS) than response, indicating their prognostic rather than predictive nature. An increase in tumor-infiltrating CD8 + T-cells and a decrease in regulatory T-cells were correlated to response, in addition to mutational load, neoantigen load, and immune-related gene expression. Immune-related adverse events were also associated frequently with a favorable response and OS. This review shows the great variety of potential biomarkers published to date, in an attempt to better understand response to ICI therapy; it also highlights the candidate markers for future research. The most promising biomarkers for response to ICI treatment are the occurrence of immune-related adverse events (especially vitiligo), lowering of lactate dehydrogenase, and increase in activated CD8 + and decrease in regulatory T-cells.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Melanoma/terapia , Neoplasias Cutâneas/terapia , Anticorpos Monoclonais/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Linfócitos T CD8-Positivos/citologia , Antígeno CTLA-4/antagonistas & inibidores , Ciclo Celular , Humanos , Imunoterapia/métodos , Prognóstico , Linfócitos T Reguladores/citologia , Resultado do Tratamento
14.
Pigment Cell Melanoma Res ; 32(4): 540-552, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30767390

RESUMO

Monobenzone is a 4-substituted phenol that can induce vitiligo and antimelanoma immunity. We investigated the influence of the chemical structure on the biological activity of a series of structurally related 4-substituted phenols. All phenols inhibited cellular melanin synthesis, and eight of ten phenols inhibited tyrosinase activity, using the MBTH assay. These phenols also induced glutathione (GSH) depletion, indicative of quinone formation and protein thiol binding, which can increase the immunogenicity of melanosomal proteins. Specific T-cell activation was found upon stimulation with phenol-exposed pigmented cells, which also reacted with unexposed cells. In contrast, 4-tertbutylphenol induced immune activation was not restricted to pigment cells, analogous to contact sensitization. We conclude that 4-substituted phenols can induce specific T-cell responses against melanocytes and melanoma cells, also acting at distant, unexposed body sites, and may confer a risk of chemical vitiligo. Conversely, these phenols may be applicable to induce specific antimelanoma immunity.


Assuntos
Imunidade , Melanoma/imunologia , Vitiligo/imunologia , Bioensaio , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Humanos , Levodopa/metabolismo , Ativação Linfocitária/imunologia , Melaninas/biossíntese , Melanoma/patologia , Melanossomas/metabolismo , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/metabolismo , Fenóis/química , Ligação Proteica , Quinonas/metabolismo , Compostos de Sulfidrila/metabolismo , Vitiligo/patologia
15.
Melanoma Res ; 29(4): 349-357, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30615012

RESUMO

The cancer/testis antigen (CTA) family is a group of antigens whose expression is restricted to male germline cells of the testis and various malignancies. This expression pattern makes this group of antigens potential targets for immunotherapy. The aim of this study was to create an overview of CTA expressed by melanoma cells at mRNA and protein level. A systematic literature search was performed in Medline (PubMed) and Embase from inception up to and including February 2018. Studies were screened for eligibility by two independent reviewers. A total of 65 full-text articles were included in the final analysis. A total of 48 CTA have been studied in melanoma. Various CTA show different expression rates in primary and metastatic tumours. Of the 48 CTA, the most studied were MAGE-A3, MAGE-A1, NY-ESO-1, MAGE-A4, SSX2, MAGE-A2, MAGE-C1/CT7, SSX1, MAGE-C2/CT10 and MAGE-A12. On average, MAGE-A3 mRNA is present in 36% of primary tumours, whereas metastatic tumours have an expression rate of 55-81%. The same applies to the protein expression rate of MAGE-A3 in primary tumours, which is reported to be at 15-37%, whereas metastatic tumours have a higher expression rate of 25-70%. This trend of increased expression in metastases compared with primary tumours is observed with MAGE-A1, MAGE-A2, MAGE-A4, MAGE-A12 and NY-ESO-1. Many CTA are expressed on melanoma. This review provides an overview of the expression frequency of CTAs in melanoma and may aid in identifying CTA as the therapeutic target for immunotherapy.


Assuntos
Antígenos de Neoplasias/metabolismo , Biomarcadores Tumorais/metabolismo , Melanoma/genética , Neoplasias Cutâneas/genética , Testículo/metabolismo , Humanos , Masculino , Melanoma/patologia , Neoplasias Cutâneas/patologia
16.
Pigment Cell Melanoma Res ; 32(1): 68-78, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30009548

RESUMO

To study the contribution of T-cell receptors (TCR) to resulting T-cell responses, we studied three different human αß TCRs, reactive to the same gp100-derived peptide presented in the context of HLA-A*0201. When expressed in primary CD8 T cells, all receptors elicited classic antigen-induced IFN-γ responses, which correlated with TCR affinity for peptide-MHC in the order T4H2 > R6C12 > SILv44. However, SILv44 elicited superior IL-17A release. Importantly, in vivo, SILv44-transgenic T cells mediated superior antitumor responses to 888-A2 + human melanoma tumor cells upon adoptive transfer into tumor-challenged mice while maintaining IL-17 expression. Modeling of the TCR ternary complexes suggested architectural differences between SILv44 and the other complexes, providing a potential structural basis for the observed differences. Overall, the data reveal a more prominent role for the T-cell receptor in defining host T-cell physiology than traditionally assumed, while parameters beyond IFN-γ secretion and TCR affinity ultimately determine the reactivity of tumor-reactive T cells.


Assuntos
Antineoplásicos/imunologia , Citocinas/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/imunologia , Antígeno gp100 de Melanoma/metabolismo , Animais , Linhagem Celular Tumoral , Humanos , Interferon gama/metabolismo , Interleucina-17/metabolismo , Camundongos Transgênicos , Modelos Moleculares , Peptídeos/metabolismo
17.
Oncoimmunology ; 7(4): e1419113, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29632737

RESUMO

Vitiligo development in melanoma patients during immunotherapy is a favorable prognostic sign and indicates breakage of tolerance against melanocytic/melanoma antigens. We investigated a novel immunotherapeutic approach of the skin-depigmenting compound monobenzone synergizing with imiquimod in inducing antimelanoma immunity and melanoma regression. Stage III-IV melanoma patients with non-resectable cutaneous melanoma metastases were treated with monobenzone and imiquimod (MI) therapy applied locally to cutaneous metastases and adjacent skin during 12 weeks, or longer. Twenty-one of 25 enrolled patients were evaluable for clinical assessment at 12 weeks. MI therapy was well-tolerated. Partial regression of cutaneous metastases was observed in 8 patients and stable disease in 1 patient, reaching the statistical endpoint of treatment efficacy. Continued treatment induced clinical response in 11 patients, including complete responses in three patients. Seven patients developed vitiligo-like depigmentation on areas of skin that were not treated with MI therapy, indicating a systemic effect of MI therapy. Melanoma-specific antibody responses were induced in 7 of 17 patients tested and melanoma-specific CD8+T-cell responses in 11 of 15 patients tested. These systemic immune responses were significantly increased during therapy as compared to baseline in responding patients. This study shows that MI therapy induces local and systemic anti-melanoma immunity and local regression of cutaneous metastases in 38% of patients, or 52% during prolonged therapy. This study provides proof-of-concept of MI therapy, a low-cost, broadly applicable and well-tolerated treatment for cutaneous melanoma metastases, attractive for further clinical investigation.

18.
Exp Dermatol ; 27(4): 393-395, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28887844

RESUMO

Aero-allergens, such as house dust mite (HDM), have been suggested to play a role in the initiation of atopic dermatitis (AD)-related skin inflammation. Here, we analysed the proliferation and the cytokine expression of blood-derived T cells from AD and healthy individuals upon HDM-allergen stimulation. The proliferating cells from healthy individuals and AD patients had a significantly different, distinct cytokine profile: in AD blood, we found increased frequencies of HDM-reactive IL-31-producing T cells, as well as a decreased Th1/Th2 and Tc1/Tc2 ratio, suggesting that allergen-specific T cells in blood of chronic AD patients are subject to pre-existent Th2-Tc2 and "Th31-Tc31" programming.


Assuntos
Antígenos de Dermatophagoides/farmacologia , Linfócitos T CD8-Positivos/metabolismo , Dermatite Atópica/sangue , Interleucinas/metabolismo , Células Th1/metabolismo , Células Th2/metabolismo , Adulto , Animais , Contagem de Linfócito CD4 , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Dermatite Atópica/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pyroglyphidae , Células Th1/imunologia , Células Th2/imunologia , Adulto Jovem
19.
Front Oncol ; 7: 233, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29034210

RESUMO

BACKGROUND: Immune checkpoint inhibitors (ICIs), targeting CTLA-4 or PD-1 molecules, have shown impressive therapeutic results. However, only 20-40% of advanced melanoma patients have durable responses to ICI, and these positive effects must be balanced against severe off-target immune toxicity and high costs. This urges the development of predictive biomarkers for ICI response to select patients with likely clinical benefit from treatment. Although many candidate biomarkers exist, a systematic overview of biomarkers and their usefulness is lacking. OBJECTIVES: Here, we systematically review the current literature of clinical data of ICI treatment to provide an overview of candidate predictive biomarkers for ICI in melanoma patients. METHODS: To identify studies on biomarkers for clinical response or survival to ICI therapy in melanoma patients, we performed a systematic search in OVID MEDLINE and retrieved 429 publications, of which 67 met the eligibility criteria. RESULTS: Blood and genomic biomarkers were mainly studied for CTLA-4 ICI, while tumor tissue markers were analyzed for both CTLA-4 and PD-1 ICI. Blood cytology and soluble factors correlated more frequently to overall survival (OS) than to response, indicating their prognostic rather than predictive nature. Systemic T-cell response and regulation markers correlated to response, but progression-free survival or OS were not analyzed. Tumor tissue analyses revealed response correlations with mutational load, neoantigen load, immune-related gene expression, and CD8+ T-cell infiltration at the invasive margin. The predictive value of PD-L1 varied, possibly due to the influence of T-cell infiltration on tumor PD-L1 expression. Genomic biomarker studies addressed CTLA-4 and other immune-related genes. CONCLUSION: This review outlines all published biomarkers for ICI therapy and highlights potential candidate markers for future research. To date, PD-L1 is the best studied biomarker for PD-1 ICI response. The most promising candidate predictive biomarkers for ICI response have not yet been identified. Variations in outcome parameters, statistical power, and analyses hampered summary of the results. Further investigation of biomarkers in larger patient cohorts using standardized objectives and outcome measures is recommended.

20.
J Dermatolog Treat ; 28(1): 86-91, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27309418

RESUMO

BACKGROUND: To date, autologous punch grafting appears to be the easiest and least expensive surgical technique for stable vitiligo and piebaldism. Punch grafting is available worldwide, with no need for specialised instruments. However, no reliable data on efficacy and safety of different punch depths and punch sizes are available. OBJECTIVE/METHODS: To compare the efficacy and safety of different punch depths and punch sizes in autologous punch grafting, a randomised controlled trial was performed in 33 patients with vitiligo or piebaldism. In each patient, four depigmented regions were allocated to: 1.5 mm deep grafts, 1.5 mm superficial grafts, 1.0 mm deep grafts, and 1.0 mm superficial grafts. Primary outcome was the total pigmented surface area. Secondary outcomes were Patients' Global Assessment (PGA) and side effects. RESULTS: Six months after grafting, 1.5 mm grafts showed a significantly larger pigmented surface area compared to 1.0-mm grafts (p < 0.001), though more side effects as well. No significant differences in the total pigmented surface between different punch depths were found. Deep grafts showed more erythema compared to superficial grafts. CONCLUSION: We recommend 1.5 mm superficial grafts in autologous punch grafting for trunk and proximal extremities in patients with stable vitiligo and piebaldism.


Assuntos
Piebaldismo/cirurgia , Transplante de Pele/métodos , Vitiligo/cirurgia , Adolescente , Adulto , Extremidades , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Tronco , Transplante Autólogo/métodos , Resultado do Tratamento , Adulto Jovem
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