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This Corrigendum relates to the following article: https://doi.org/10.2340/actadv.v104.13381.
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Carcinoma de Células Escamosas , Queratoacantoma , Neoplasias Cutáneas , Humanos , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/metabolismo , Queratoacantoma/patología , Queratoacantoma/metabolismo , Queratoacantoma/inmunología , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/metabolismo , Masculino , Femenino , Anciano , Proteínas de Punto de Control Inmunitario/metabolismo , Persona de Mediana Edad , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/metabolismo , Inmunohistoquímica , Anciano de 80 o más AñosRESUMEN
BACKGROUND: To assess the distribution characteristics of immune infiltration and lymphovascular invasion in breast cancer skin recurrence patients. METHODS: We retrospectively analyzed the clinicopathological data of patients who underwent radical surgery for primary breast cancer and experienced skin recurrence between January 2001 and April 2019. Immune and lymphovascular biomarkers were quantified in primary breast cancers, skin lesions and visceral metastatic lesions. Differences in biomarkers distribution between matched tissues were statistically analyzed using the Wilcoxon signed-rank test and Kruskal-Wallis one-way ANOVA. RESULTS: A total of 71 female breast cancer patients were reviewed in this study. Our study found that the expression levels of various lymphocyte immune markers in primary tumor specimens were higher than those in skin recurrences. The expression of CD8, CD57 and CD31 in primary breast cancer was higher than those in the skin. Compared to visceral metastatic lesions, D2-40 was highly expressed in the skin, while CD8 tended to decrease. In the skin specimens, the expression of CD8 (P < 0.001), FOXP3 (P = 0.006) and CD68 (P < 0.001) in the intratumoral area was higher, while the expression of CD57 (P < 0.001) was higher in the peritumoral area. Analyzing specimens from the same patient at different time points of skin progression, it was found that the expression of peritumoral CD4 decreased (P = 0.044) as the disease progressed. The low expression of D2-40 and CD163 in the skin lesions suggested a decrease in DFS. CONCLUSION: The immune microenvironment of breast cancer skin recurrence may be in a state of suppression, and this suppression may intensify with disease progression. The pattern of skin recurrence may be more inclined toward lymphatic invasion. Our study provides new insights into the biological behaviors of this disease and its response to immunotherapy.
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Neoplasias de la Mama , Linfocitos Infiltrantes de Tumor , Recurrencia Local de Neoplasia , Neoplasias Cutáneas , Humanos , Femenino , Neoplasias de la Mama/patología , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/metabolismo , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/metabolismo , Persona de Mediana Edad , Estudios Retrospectivos , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/metabolismo , Anciano , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Adulto , Metástasis Linfática/patología , Metástasis Linfática/inmunología , Biomarcadores de Tumor/metabolismo , Microambiente Tumoral/inmunología , Invasividad Neoplásica , PronósticoRESUMEN
Bullous pemphigoid (BP) is the most common autoimmune bullous disease: it most commonly affects individuals over 70 years old and impacts severely on their quality of life. BP represents a paradigm for an organ-specific autoimmune disease and is characterized by circulating IgG autoantibodies to hemidesmosomal components: BP180 and BP230. While the crucial role of these autoantibodies in triggering BP inflammatory cascade is fully acknowledged, many ancillary etiological mechanisms need to be elucidated yet. Cutaneous melanoma is due to a malignant transformation of skin melanocytes, that produce and distribute pigments to surrounding keratinocytes. Melanoma is the most fatal skin cancer because of its increasing incidence and its propensity to metastasize. Several data such as: i) reported cases of concomitant melanoma and BP; ii) results from association studies; iii) BP onset following immune check-point inhibitors therapy; iv) expression of BP antigens in transformed melanocytes; and vi) circulating autoantibodies to BP antigens in melanoma patients suggest an intriguing, although unproven, possible association between melanoma and BP. However, a possible causative link is still debated and the putative pathogenetic mechanism underlying this association is unclear. This review aims to describe and discuss the possible relationship between BP and melanoma and give an overview of the speculations for or against this association. Of note, if demonstrated, this association could unwrap considerations of clinical relevance that represent new research frontiers.
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Autoanticuerpos , Autoantígenos , Melanoma , Penfigoide Ampolloso , Humanos , Penfigoide Ampolloso/inmunología , Penfigoide Ampolloso/etiología , Melanoma/inmunología , Melanoma/etiología , Autoanticuerpos/inmunología , Autoanticuerpos/sangre , Autoantígenos/inmunología , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/etiología , Colágeno Tipo XVII , Colágenos no Fibrilares/inmunología , Melanocitos/inmunología , Melanocitos/patología , Animales , Relevancia ClínicaRESUMEN
Asthma is a respiratory disorder caused by airway inflammation which may worsen after allergen exposure. Recent cohort studies demonstrate a positive association between skin cancer and asthma or hay fever (allergy to outdoor allergens such as pollen). Nationally-representative data for adults in the United States remains limited. We aimed to characterize skin cancer prevalence among individuals in the United States who have asthma or hay fever. To achieve this aim, we extracted nationwide cross-sectional data from 16,277 adult participants (total survey-weighted sample = 174,765,931) of the Third National Health and Nutrition Examination Survey from 1988 to 1994. This study uses survey-weighted regression to compare the nationwide prevalence of skin cancer among participants with or without a history of asthma or hay fever. Sensitivity analysis examined the influence of sex, 25-hydroxyvitamin D, chronic bronchitis or emphysema, geographical region, urban proximity, and oral glucocorticoid use. Of the included participants, the age-adjusted prevalence of skin cancer was 7.2%, similar to national estimates. Skin cancer prevalence was higher among participants who had asthma with hay fever (adjusted prevalence ratio, 1.79; 95% confidence interval, 1.16, 2.76), but not among participants with asthma only or hay fever only. Similarly, skin cancer prevalence was higher for those with asthma and positive pollen allergen skin prick testing (SPT), but not for those with hay fever and positive pollen SPT. No association was noted between skin cancer and wheezing triggered by pollen. Hay fever or immunoglobulin-E sensitization to pollen may increase skin cancer prevalence among individuals with a history of asthma.
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Asma , Encuestas Nutricionales , Rinitis Alérgica Estacional , Neoplasias Cutáneas , Humanos , Estudios Transversales , Masculino , Rinitis Alérgica Estacional/epidemiología , Rinitis Alérgica Estacional/inmunología , Rinitis Alérgica Estacional/diagnóstico , Femenino , Adulto , Persona de Mediana Edad , Estados Unidos/epidemiología , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/diagnóstico , Prevalencia , Asma/epidemiología , Asma/inmunología , Asma/diagnóstico , Alérgenos/inmunología , Alérgenos/efectos adversos , Pruebas Cutáneas , Anciano , Adulto Joven , Polen/inmunología , Polen/efectos adversos , Factores de RiesgoRESUMEN
Melanoma is the most aggressive and deadly form of skin cancer, and its incidence has been steadily increasing over the past few decades, particularly in the Caucasian population. Immune checkpoint inhibitors (ICI), anti-PD-1 monotherapy or in combination with anti-CTLA-4, and more recently, anti-PD-1 plus anti-LAG-3 have changed the clinical evolution of this disease. However, a significant percentage of patients do not benefit from these therapies. Therefore, to improve patient selection, it is imperative to look for novel biomarkers. Immune subsets, particularly the quantification of lymphocyte T populations, could contribute to the identification of ICI responders. The main purpose of this review is to thoroughly examine significant published data on the potential role of lymphocyte T subset distribution in peripheral blood (PB) or intratumorally as prognostic and predictive of response biomarkers in advanced melanoma patients treated with ICI regardless of BRAFV600 mutational status.
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Inhibidores de Puntos de Control Inmunológico , Melanoma , Subgrupos de Linfocitos T , Humanos , Melanoma/tratamiento farmacológico , Melanoma/inmunología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/efectos de los fármacos , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/inmunología , Pronóstico , Biomarcadores de Tumor , Resultado del TratamientoRESUMEN
AIM: We aimed to explore the impact of DNA methylation alterations on the DNA damage response (DDR) in melanoma prognosis and immunity. MATERIAL & METHODS: Different melanoma cohorts with molecular and clinical data were included. RESULTS: Hierarchical clustering utilizing different combinations of DDR-relevant CpGs yielded distinct melanoma subtypes, which were characteristic of different prognoses, transcriptional function profiles of DDR, and immunity and immunotherapy responses but were associated with similar tumor mutation burdens. We then constructed and validated a clinically applicable 4-CpG risk-score signature for predicting survival and immunotherapy response. CONCLUSION: Our study describes the close interrelationship among DNA methylation, DDR machinery, local tumor immune status, melanoma prognosis, and immunotherapy response.
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Daño del ADN , Metilación de ADN , Melanoma , Melanoma/genética , Melanoma/inmunología , Melanoma/mortalidad , Humanos , Pronóstico , Inmunoterapia/métodos , Islas de CpG , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Regulación Neoplásica de la Expresión Génica/inmunología , MutaciónRESUMEN
BACKGROUND: Advanced Merkel cell carcinoma (MCC) has a high response rate to immune checkpoint blockade (ICB) therapy, but the durability of responses once treatment is discontinued remains unclear. We therefore reviewed the long-term outcomes of advanced patients with MCC who discontinued ICB treatment after achieving favorable initial response. METHODS: We performed a retrospective review of advanced patients with MCC treated at a single high-volume referral center, including all patients who received at least one dose of anti-programmed death receptor 1 (ligand) monotherapy for unresectable or metastatic disease, achieved stable disease (SD) or better, and discontinued treatment for a reason other than disease progression. RESULTS: Of 195 advanced patients with MCC treated with ICB, we identified 45 who met the study criteria. Of these, 21 (46.6%) had a complete response (CR) to initial ICB treatment, 23 (51.1%) a partial response and 1 (2.2%) SD. 25 (55.6%) patients discontinued ICB electively and 20 (44.4%) discontinued due to toxicity. In total, 21 of the 45 patients (46.6%) experienced disease progression at a median of 11.3 months (range 2.1-22.7 months) from ICB cessation. There was a lower rate of progression in patients who achieved CR versus non-CR (23.8% vs 66.7%, p=0.006) and a trend towards a lower rate in those who discontinued electively versus due to toxicity (36.0% vs 60.0%, p=0.14). There was a higher risk for progression in patients with viral positive MCC compared with viral negative MCC (75.0 vs 30.8%, p=0.02). 16 of the 21 patients who experienced progression were retreated subsequently with ICB therapy, including both single-agent rechallenge (12) and escalation to combination ICB (4). 11 of 15 evaluable ICB-retreated patients (73.3%) achieved an objective response. CONCLUSIONS: Patients with advanced MCC have a substantial risk of disease progression following treatment discontinuation despite initial favorable ICB response, particularly in those that achieve less than a CR. Most of these patients maintain sensitivity to retreatment with the same drug class. Virus-positive MCC may be a risk factor for post-discontinuation relapse, which should be validated in future studies.
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Carcinoma de Células de Merkel , Inhibidores de Puntos de Control Inmunológico , Humanos , Carcinoma de Células de Merkel/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Masculino , Femenino , Anciano , Persona de Mediana Edad , Estudios Retrospectivos , Anciano de 80 o más Años , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/inmunología , Resultado del TratamientoRESUMEN
Image-guided percutaneous cryoablation is an established minimally invasive oncologic treatment. We hypothesized that cryoablation may modify the immune microenvironment through direct modulation of the tumor, thereby generating an anti-tumor response in tumors refractory to immune checkpoint inhibition (ICI). In this non-randomized phase II single-center study (NCT03290677), subjects with unresectable melanoma progressing on ICI underwent cryoablation of an enlarging metastasis, and ICI was continued for a minimum of two additional cycles. The primary endpoints were safety, feasibility and tumor response in non-ablated lesions. From May 2018 through July 2020, 17 patients were treated on study. The study met its primary endpoints with the combination strategy found to be safe and feasible with an objective response rate of 23.5% and disease control rate of 41% (4 partial response, 3 stable disease). Our data support further study of this synergistic therapeutic approach.
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Criocirugía , Inhibidores de Puntos de Control Inmunológico , Melanoma , Humanos , Melanoma/tratamiento farmacológico , Melanoma/patología , Melanoma/cirugía , Melanoma/inmunología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Criocirugía/métodos , Femenino , Masculino , Persona de Mediana Edad , Anciano , Progresión de la Enfermedad , Adulto , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/cirugía , Microambiente Tumoral/inmunología , Metástasis de la Neoplasia , Resultado del Tratamiento , Terapia Combinada , Anciano de 80 o más AñosRESUMEN
The innate immune system, composed of neutrophils, basophils, eosinophils, myeloid-derived suppressor cells (MDSCs), macrophages, dendritic cells (DCs), mast cells (MCs), and innate lymphoid cells (ILCs), is the first line of defense. Growing evidence demonstrates the crucial role of innate immunity in tumor initiation and progression. Several studies support the idea that innate immunity, through the release of pro- and/or anti-inflammatory cytokines and tumor growth factors, plays a significant role in the pathogenesis, progression, and prognosis of cutaneous malignant melanoma (MM). Cutaneous melanoma is the most common skin cancer, with an incidence that rapidly increased in recent decades. Melanoma is a highly immunogenic tumor, due to its high mutational burden. The metastatic form retains a high mortality. The advent of immunotherapy revolutionized the therapeutic approach to this tumor and significantly ameliorated the patients' clinical outcome. In this review, we will recapitulate the multiple roles of innate immune cells in melanoma and the related implications for immunotherapy.
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Inmunidad Innata , Inmunoterapia , Melanoma , Humanos , Melanoma/terapia , Melanoma/inmunología , Melanoma/patología , Inmunoterapia/métodos , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/terapia , Neoplasias Cutáneas/patología , Animales , Células Dendríticas/inmunología , Melanoma Cutáneo Maligno , Mastocitos/inmunologíaRESUMEN
The occurrence and progression of skin cutaneous melanoma (SKCM) is strongly associated with immune cells infiltrating the tumor microenvironment (TME). This study examined the expression, prognosis, and immune relevance of SIGLEC9 in SKCM using multiple online databases. Analysis of the GEPIA2 and Ualcan databases revealed that SIGLEC9 is highly expressed in SKCM, and patients with high SIGLEC9 expression had improved overall survival (OS). Furthermore, the mutation rate of SIGLEC9 in SKCM patients was found to be 5.41%, the highest observed. The expression of SIGLEC9 was positively correlated with macrophages, neutrophils and B cells, CD8 + T cells, CD4 + T cells, and dendritic cells, according to TIMER. Based on TCGA-SKCM data, we verified that high SIGLEC9 expression is closely associated with a good prognosis for SKCM patients, including overall survival, progression-free interval, and disease-specific survival. This positive prognosis could be due to the infiltration of immune cells into the TME. Additionally, our analysis of single-cell transcriptome data revealed that SIGLEC9 not only played a role in the normal skin immune microenvironment, but is also highly expressed in immune cell subpopulations of SKCM patients, regulating the immune response to tumors. Our findings suggest that the close association between SIGLEC9 and SKCM prognosis is primarily mediated by its effect on the tumor immune microenvironment.
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Biomarcadores de Tumor , Melanoma , Neoplasias Cutáneas , Microambiente Tumoral , Humanos , Microambiente Tumoral/inmunología , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/mortalidad , Melanoma/inmunología , Melanoma/genética , Melanoma/mortalidad , Melanoma/patología , Pronóstico , Biomarcadores de Tumor/genética , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico/metabolismo , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico/genética , Melanoma Cutáneo Maligno , Antígenos CD/genética , Antígenos CD/metabolismo , Linfocitos Infiltrantes de Tumor/inmunologíaRESUMEN
Merkel cell polyomavirus (MCPyV) is the causative agent of the majority of Merkel cell carcinomas (MCC). The virus has limited coding capacity, with its early viral proteins, large T (LT) and small T (sT), being multifunctional and contributing to infection and transformation. A fundamental difference in early viral gene expression between infection and MCPyV-driven tumorigenesis is the expression of a truncated LT (LTtr) in the tumor. In contrast, sT is expressed in both conditions and contributes significantly to oncogenesis. Here, we identified novel functions of early viral proteins by performing genome-wide transcriptome and chromatin studies in primary human fibroblasts. Due to current limitations in infection and tumorigenesis models, we mimic these conditions by ectopically expressing sT, LT or LTtr, individually or in combination, at different time points. In addition to its known function in cell cycle and inflammation modulation, we reveal a fundamentally new function of sT. We show that sT regulates the type I interferon (IFN) response downstream of the type I interferon receptor (IFNAR) by interfering with the interferon-stimulated gene factor 3 (ISGF3)-induced interferon-stimulated gene (ISG) response. Expression of sT leads to a reduction in the expression of interferon regulatory factor 9 (IRF9) which is a central component of the ISGF3 complex. We further show that this function of sT is conserved in BKPyV. We provide a first mechanistic understanding of which early viral proteins trigger and control the type I IFN response, which may influence MCPyV infection, persistence and, during MCC progression, regulation of the tumor microenvironment.
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Carcinoma de Células de Merkel , Evasión Inmune , Interferón Tipo I , Poliomavirus de Células de Merkel , Infecciones por Polyomavirus , Transducción de Señal , Infecciones Tumorales por Virus , Humanos , Poliomavirus de Células de Merkel/inmunología , Interferón Tipo I/metabolismo , Interferón Tipo I/inmunología , Carcinoma de Células de Merkel/virología , Carcinoma de Células de Merkel/inmunología , Transducción de Señal/inmunología , Infecciones por Polyomavirus/inmunología , Infecciones por Polyomavirus/virología , Infecciones Tumorales por Virus/inmunología , Infecciones Tumorales por Virus/virología , Evasión Inmune/inmunología , Antígenos Virales de Tumores/metabolismo , Antígenos Virales de Tumores/inmunología , Antígenos Virales de Tumores/genética , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/virología , Neoplasias Cutáneas/metabolismo , Fibroblastos/virología , Fibroblastos/metabolismo , Fibroblastos/inmunologíaRESUMEN
Melanoma is the deadliest form of skin cancer in the United States, with its incidence rates rising in older populations. As the immune system undergoes age-related changes, these alterations can significantly influence tumor progression and the effectiveness of cancer treatments. Recent advancements in understanding immune checkpoint molecules have paved the way for the development of innovative immunotherapies targeting solid tumors. However, the aging tumor microenvironment can play a crucial role in modulating the response to these immunotherapeutic approaches. This review seeks to examine the intricate relationship between age-related changes in the immune system and their impact on the efficacy of immunotherapies, particularly in the context of melanoma. By exploring this complex interplay, we hope to elucidate potential strategies to optimize treatment outcomes for older patients with melanoma, and draw parallels to other cancers.
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Progresión de la Enfermedad , Inmunoterapia , Melanoma , Neoplasias Cutáneas , Microambiente Tumoral , Humanos , Microambiente Tumoral/inmunología , Melanoma/inmunología , Melanoma/patología , Melanoma/tratamiento farmacológico , Melanoma/terapia , Inmunoterapia/métodos , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/terapia , Animales , Envejecimiento/inmunología , Factores de Edad , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacologíaRESUMEN
BACKGROUND: CD8+ T cells have been recognized as crucial factors in the prognosis of melanoma. However, there is currently a lack of gene markers that accurately describe their characteristics and functions in acral melanoma (AM), which hinders the development of personalized medicine. METHODS: Firstly, we explored the composition differences of immune cells in AM using single-cell RNA sequencing (scRNA-seq) data and comprehensively characterized the immune microenvironment of AM in terms of composition, developmental differentiation, function, and cell communication. Subsequently, we constructed and validated a prognostic risk scoring model based on differentially expressed genes (DEGs) of CD8+ T cells using the TCGA-SKCM cohort through Lasso-Cox method. Lastly, immunofluorescence staining was performed to validate the expression of four genes (ISG20, CCL4, LPAR6, DDIT3) in AM and healthy skin tissues as included in the prognostic model. RESULTS: The scRNA-seq data revealed that memory CD8+ T cells accounted for the highest proportion in the immune microenvironment of AM, reaching 70.5%. Cell-cell communication analysis showed extensive communication relationships among effector CD8+ T cells. Subsequently, we constructed a prognostic scoring model based on DEGs derived from CD8+ T cell sources. Four CD8+ T cell-related genes were included in the construction and validation of the prognostic model. Additionally, immunofluorescence results demonstrated that ISG20 and CCL4 were downregulated, while LPAR6 and DDIT3 were upregulated in AM tissues compared to normal skin tissues. CONCLUSION: Identifying biomarkers based on the expression levels of CD8+ T cell-related genes may be an effective approach for establishing prognostic models in AM patients. The independently prognostic risk evaluation model we constructed provides new insights and theoretical support for immunotherapy in AM.
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Linfocitos T CD8-positivos , Melanoma , Análisis de la Célula Individual , Neoplasias Cutáneas , Microambiente Tumoral , Humanos , Linfocitos T CD8-positivos/inmunología , Melanoma/genética , Melanoma/inmunología , Melanoma/patología , Pronóstico , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Femenino , Masculino , Análisis de Secuencia de ARN , Persona de Mediana Edad , Biomarcadores de Tumor/genética , Medición de RiesgoRESUMEN
BACKGROUND: Melanoma is an aggressive malignancy primarily impacting the skin, mucous membranes, and pigment epithelium. The tumor microbial microenvironment encompasses both the microorganisms inhabiting the tumor vicinity and the environmental factors influencing their interactions. Emerging evidence highlights the pivotal role of the microbial immune microenvironment in melanoma. METHODS: We conducted an extensive review of scholarly works published from 2012 to 2022, utilizing The Web of Science Core Collection. Subsequently, we employed analytical tools such as VOSviewer, CiteSpace, and the R programming language to scrutinize prevailing research patterns within this domain. RESULTS: A sum of 513 articles were pinpointed, with notable input coming from the United States and China. Harvard University stood out as the top-contributing institution, while the journal Science received the most citations. Current research within this sphere chiefly focuses on two principal domains: the gut microbiota and the PD-L1 pathway concerning melanoma treatment. CONCLUSION: The study offers an extensive analysis and overview of the worldwide research landscape concerning the immune microenvironment with a focus on microbes in melanoma. It underscores the promising prospects for harnessing the microbial immune microenvironment's potential in melanoma. These findings furnish valuable insights and guidance for advancing scientific inquiry and refining clinical approaches within this dynamic field.
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Bibliometría , Melanoma , Neoplasias Cutáneas , Microambiente Tumoral , Melanoma/inmunología , Melanoma/microbiología , Humanos , Microambiente Tumoral/inmunología , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/microbiología , Microbioma Gastrointestinal , Investigación BiomédicaRESUMEN
BACKGROUND: Neutrophil extracellular traps (NETs) are related to the prognosis of cancer patients. Nevertheless, the potential prognostic values of NETs in skin cutaneous melanoma (SKCM) remains largely unknown. MATERIALS AND METHODS: The NET-related gene signature was constructed by LASSO Cox regression analysis using the TCGA-SKCM cohort. The overall survival (OS) and immune status in SKCM patients between the high- and low-NET score (high-score, low-score) groups were explored. The scRNA-seq dataset GSE115978 was used to understand the role of NET score in SKCM at single cell resolution. RESULTS: A five NET genes-based signature (TLR2, CLEC6A, PDE4B, SLC22A4 and CYP4F3) was constructed as the NET-related prognostic model for SKCM. The OS of SKCM patients with low-score was better than that in patients with high-score. Additionally, NET score was negatively associated with infiltration of some immune cells (e.g. type I Macrophages, CD8-T cells, CD4-T cells). Moreover, patients with high-score had low stromal, immune and ESTIMATE scores. Furthermore, drug sensitivity analysis results showed that Lapatinib, Trametinib and Erlotinib may have better therapeutic advantages in patients with high-score. CONCLUSION: We established a NET-related five gene signature in SKCM and found that the NET-related signature may exhibit a good predictive ability for SKCM prognosis. The NET score may not only predict the survival outcome and drug sensitivity in SKCM, but also reflect the immune conditions of SKCM patients.
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Trampas Extracelulares , Melanoma , Neoplasias Cutáneas , Humanos , Melanoma/genética , Melanoma/inmunología , Melanoma/mortalidad , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Pronóstico , Masculino , Femenino , Persona de Mediana Edad , Melanoma Cutáneo Maligno , Anciano , NeutrófilosRESUMEN
BACKGROUND: Melanoma is a highly aggressive form of skin cancer. The existence of cancer stem cells (CSCs) and tumor immune evasion are two major causes of melanoma progression, but no effective treatment has been found at present. Astragalus polysaccharide (APS) is a principal active component derived from Astragalus membranaceus, showing anti-tumor effects in various tumors including melanoma. However, the underlying mechanism is still unclear. METHODS: The regulation of APS on self-renewal ability and CSC markers expression in melanoma stem cells (MSCs) was measured by tumor sphere formation and tumorigenicity assays, RT-qPCR, and western blot. Flow cytometry was conducted to evaluate the activation of immune system by APS in melanoma mice. Further, the mechanism was explored based on PD-L1 overexpression and knock-down B16 cells. RESULTS: APS attenuated the tumor sphere formation of MSCs in vitro as well as the tumorigenicity in vivo. It also decreased the expression of CD133, BMI1 and CD47. Based on the PD-L1 overexpression and knock-down B16 cells, it was confirmed that APS inhibited the induction of MSCs by down-regulating PD-L1 expression. Meanwhile, APS increased the infiltration of CD4+ and CD8+T cells in tumor tissues because of its inhibitory effect on PD-L1. CONCLUSIONS: APS inhibited MSC induction and overcame tumor immune evasion through reducing PD-L1 expression. This study provided compelling evidence that APS could be a prospective therapeutic agent for treating melanoma.
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Antígeno B7-H1 , Melanoma Experimental , Células Madre Neoplásicas , Polisacáridos , Antígeno B7-H1/metabolismo , Animales , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/inmunología , Ratones , Polisacáridos/farmacología , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/inmunología , Melanoma Experimental/metabolismo , Melanoma Experimental/patología , Escape del Tumor/efectos de los fármacos , Línea Celular Tumoral , Ratones Endogámicos C57BL , Humanos , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/metabolismo , Melanoma/tratamiento farmacológico , Melanoma/metabolismo , Melanoma/patología , Melanoma/inmunología , Planta del Astrágalo/química , Evasión InmuneAsunto(s)
Micosis Fungoide , Parapsoriasis , Receptores de Antígenos de Linfocitos T , Neoplasias Cutáneas , Humanos , Micosis Fungoide/genética , Micosis Fungoide/patología , Micosis Fungoide/inmunología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/inmunología , Parapsoriasis/genética , Parapsoriasis/patología , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , Masculino , Femenino , Persona de Mediana Edad , Factores de TiempoRESUMEN
Skin cancer has the highest incidence of all cancers, and their incidence are increasing in both melanoma and non-melanoma skin cancers. Alternative adjuvant treatment strategies appropriate for their management are needed. Modifiable lifestyle factors influence disease outcomes, either improving or worsening outcomes. Exercise is an example of a modifiable lifestyle factor, and can be prescribed as an adjuvant therapy in other cancer types to improve immune function and overall clinical outcomes. The initial aim of the review was to investigate the T-cell specific mechanisms of exercise which affect clinical/disease outcomes in skin cancer. Study quality was assessed by a modified Covidence quality assessment template with animal-model study specific criteria. A total of 10 articles were included; all articles were murine model studies investigating melanoma. Eight studies (n=8) employed a randomised controlled trial design, with two bio-informatics studies, and one study using human data which could solidify a link to human health. While the review focussed initially on T-cells, many studies reported significant changes in NK cells, and as they share the same haematopoietic lineage/ common lymphoid progenitor as T cells, the data was included in the analyses. Most studies indicated that exercise reduced melanoma tumour burden. Exercising prior to melanoma inoculation was most effective for delaying carcinogenesis and reducing tumour burden. Synergism was a topic identified in studies; PD-1/PD-L1 treatment, and exercise were not synergistic. Conversely, exercise and mental stimulation were synergistic, and the temperature at which exercise was conducted significantly reduced tumour burden. Several murine studies reported that exercise improved clinical outcomes in melanoma, and that long-term exercise was more effective in reducing tumour burden. Further studies are required to investigate this relationship in humans, and in other types of skin cancer.
Asunto(s)
Ejercicio Físico , Células Asesinas Naturales , Neoplasias Cutáneas , Linfocitos T , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/terapia , Humanos , Animales , Células Asesinas Naturales/inmunología , Ejercicio Físico/fisiología , Linfocitos T/inmunología , Melanoma/inmunología , Melanoma/terapia , Ratones , Modelos Animales de EnfermedadRESUMEN
Introduction: Advanced cutaneous melanoma is a skin cancer characterized by a poor prognosis and high metastatic potential. During metastatic spread, melanoma cells often undergo dedifferentiation toward an invasive phenotype, resulting in reduced expression of microphthalmia-associated transcription factor (MITF)-dependent melanoma antigens and facilitating immune escape. Tumor Necrosis Factor (TNF) is known to be a key factor in melanoma dedifferentiation. Interestingly, accumulating evidence suggests that TNF may play a role in melanoma progression and resistance to immunotherapies. Additionally, TNF has been identified as a potent regulator of sphingolipid metabolism, which could contribute to melanoma aggressiveness and the process of melanoma dedifferentiation. Methods: We conducted RNA sequencing and mass spectrometry analyses to investigate TNF-induced dedifferentiation in two melanoma cell lines. In vitro experiments were performed to manipulate sphingolipid metabolism using genetic or pharmacologic alterations in combination with TNF treatment, aiming to elucidate the potential involvement of this metabolism in TNF-induced dedifferentiation. Lastly, to evaluate the clinical significance of our findings, we performed unsupervised analysis of plasma sphingolipid levels in 48 patients receiving treatment with immune checkpoint inhibitors, either alone or in combination with anti-TNF therapy. Results: Herein, we demonstrate that TNF-induced melanoma cell dedifferentiation is associated with a global modulation of sphingolipid metabolism. Specifically, TNF decreases the expression and activity of acid ceramidase (AC), encoded by the ASAH1 gene, while increasing the expression of glucosylceramide synthase (GCS), encoded by the UGCG gene. Remarkably, knockdown of AC alone via RNA interference is enough to induce melanoma cell dedifferentiation. Furthermore, treatment with Eliglustat, a GCS inhibitor, inhibits TNF-induced melanoma cell dedifferentiation. Lastly, analysis of plasma samples from patients treated with immune checkpoint inhibitors, with or without anti-TNF therapy, revealed significant predictive sphingolipids. Notably, the top 8 predictive sphingolipids, including glycosphingolipids, were associated with a poor response to immunotherapy. Discussion: Our study highlights that ceramide metabolism alterations are causally involved in TNF-induced melanoma cell dedifferentiation and suggests that the evolution of specific ceramide metabolites in plasma may be considered as predictive biomarkers of resistance to immunotherapy.