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1.
Dermatol Clin ; 41(1): 49-63, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36410983

RESUMO

Melanoma is the most lethal form of skin cancer although surgery is often curative when combined with early screening and prevention. In recurrent or advanced cancer, the emergence of chemotherapy, targeted therapy, and immune checkpoint inhibitors has demonstrated promising clinical outcomes. Such approaches can remarkably halt the progression of disease for many years, although are limited by the acquisition of resistance. The development and approval of combination therapies has further changed the treatment paradigm for certain melanomas. This review focuses on the current state of melanoma epidemiology and recent advancements in melanoma screening, histopathological classification, staged excision (i.e. wide local excision, sentinel lymph node biopsy, and Mohs micrographic surgery), and systemic treatment.


Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Medicina Molecular , Melanoma/diagnóstico , Melanoma/terapia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/terapia , Biópsia de Linfonodo Sentinela , Cirurgia de Mohs
2.
Front Immunol ; 13: 1039565, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36341357

RESUMO

Background: Skin cutaneous melanoma (SKCM) is the most frequently encountered tumor of the skin. Immunotherapy has opened a new horizon in melanoma treatment. We aimed to construct a CD8+ T cell-associated immune gene prognostic model (CDIGPM) for SKCM and unravel the immunologic features and the benefits of immunotherapy in CDIGPM-defined SKCM groups. Method: Single-cell SKCM transcriptomes were utilized in conjunction with immune genes for the screening of CD8+ T cell-associated immune genes (CDIGs) for succeeding assessment. Thereafter, through protein-protein interaction (PPI) networks analysis, univariate COX analysis, and multivariate Cox analysis, six genes (MX1, RSAD2, IRF2, GBP2, IFITM1, and OAS2) were identified to construct a CDIGPM. We detected cell proliferation of SKCM cells transfected with IRF2 siRNA. Then, we analyzed the immunologic features and the benefits of immunotherapy in CDIGPM-defined groups. Results: The overall survival (OS) was much better in low-CDIGPM group versus high CDIGPM group in TCGA dataset and GSE65904 dataset. On the whole, the results unfolded that a low CDIGPM showed relevance to immune response-correlated pathways, high expressions of CTLA4 and PD-L1, a high infiltration rate of CD8+ T cells, and more benefits from immunotherapy. Conclusion: CDIGPM is an good model to predict the prognosis, the potential immune escape from immunotherapy for SKCM, and define immunologic and molecular features.


Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/genética , Melanoma/terapia , Melanoma/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/terapia , Neoplasias Cutâneas/metabolismo , Linfócitos T CD8-Positivos , Prognóstico , Imunoterapia
3.
STAR Protoc ; 3(4): 101826, 2022 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-36386880

RESUMO

Liquid metals are increasingly applied in drug delivery, in vivo imaging, and biosensing. Herein, we describe a surface modification strategy, where cell membrane is introduced to encapsulate gallium (Ga) particles. We detail preparation steps of Ga microparticles by sonication, followed by Ga microparticles coating with purified tumor cell membranes and morphological assessment using TEM and cryo-TEM. We further describe cell uptake and establishment of tumor-bearing mouse models and steps to assess in vitro cytotoxicity and in vivo antitumor cryotherapy. For complete details on the use and execution of this protocol, please refer to Wang et al. (2022).


Assuntos
Ablação por Cateter , Criocirurgia , Gálio , Melanoma , Animais , Camundongos , Gálio/farmacologia , Melanoma/terapia , Membrana Celular
4.
Curr Oncol ; 29(10): 7388-7395, 2022 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-36290857

RESUMO

Immunotherapy, the modern oncological treatment with immune checkpoint inhibitors (ICIs), has been part of the clinical practice for malignant melanoma for more than a decade. Anti-cytotoxic T-lymphocyte antigen 4 (CTLA4), anti-programmed cell death Protein 1 (PD-1), or anti programmed death-ligand 1 (PD-L1) agents are currently part of the therapeutic arsenal of metastatic or relapsed disease in numerous cancers; more recently, they have also been evaluated and validated as consolidation therapy in the advanced local stage. The combination with radiotherapy, a treatment historically considered loco-regional, changes the paradigm, offering-via synergistic effects-the potential to increase immune-mediated tumor destruction. However, the fragile balance between the tumoricidal effects through immune mechanisms and the immunosuppression induced by radiotherapy means that, in the absence of ICI, the immune-mediated potentiation effect of radiotherapy at a distance from the site of administration is rare. Through analysis of the preclinical and clinical data, especially the evidence from the PACIFIC clinical trial, we can consider that hypofractionated irradiation and reduction of the irradiated volume, in order to protect the immune-infiltrated tumor microenvironment, performed concurrently with the immunotherapy or a maximum of 2 weeks before the start of ICI treatment, could bring maximum benefits. In addition, avoiding radiation-induced lymphopenia (RILD) by protecting some anatomical lymphoid structures or large blood vessels, as well as the use of irradiation of partial tumor volumes, even in plurimetastatic disease, for the conversion of a "cold" immunological tumor into a "hot" immunological tumor are modern concepts of radiotherapy in the era of immunotherapy. Low-dose radiotherapy could also be proposed in plurimetastatic cases, the effect being different (modeling of the TME) from that of high doses per fraction irradiation (cell death with release of antigens that facilitates immune-mediated cell death).


Assuntos
Melanoma , Receptor de Morte Celular Programada 1 , Humanos , Antígeno B7-H1 , Antígeno CTLA-4 , Inibidores de Checkpoint Imunológico , Imunoterapia , Melanoma/terapia , Microambiente Tumoral
5.
Tidsskr Nor Laegeforen ; 142(15)2022 10 25.
Artigo em Inglês, Norueguês | MEDLINE | ID: mdl-36286571

RESUMO

Melanoma is a relatively common diagnosis, both in the primary and specialist health service. Ongoing research and new evidence base means that the recommendations for investigation and treatment are continually changing. This can lead to uncertainty among doctors who do not treat this patient group regularly. In this clinical review we give a summary of the latest recommendations, primarily aimed at general practitioners, dermatologists and doctors in local hospitals.


Assuntos
Melanoma , Médicos , Neoplasias Cutâneas , Humanos , Melanoma/diagnóstico , Melanoma/terapia , Especialização , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/terapia
7.
Acta Dermatovenerol Croat ; 30(2): 82-88, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36254539

RESUMO

Mucosal melanoma, or so-called mucosal-oral melanoma is a rare but serious diagnostic and therapeutic problem. The "primary mixed" mucocutaneous forms of melanoma, which affect both the mucosa and the adjacent skin, are also particularly problematic and rare. Given that the staging, diagnosis, and treatment of mucosal (oral) melanoma differs from that of cutaneous melanoma, staging in mixed melanoma (primary mucocutaneous melanoma) as well as decisions for each subsequent diagnostic and therapeutic step should be individualized and modified according to the recommendations of the respective two classifications (for cutaneous but also mucosal melanomas), while at the same time or at least to a large extent overlapping with them. In practice, the following paradoxes occur during staging - there are melanomas with the same tumor thickness, but in different stages, which should be treated in a different, consensus-based way. At the same time, it would be appropriate for the surgical interventions to be in accordance with the patient's wishes for minimal trauma/reduced risk of developing facial disproportion. We present the case of a 69-year-old patient with a newly-developed lesion in the area of the mucosa of the upper lip and adjacent skin, which was identified as a primary mucocutaneous form of melanoma after surgical removal. The complex pathogenesis of the disease is discussed herein, emphasizing the role of UV radiation, iatrogenic immunosuppression with mycophenolate mofetil, tacrolimus, and prednisolone (due to severe glomerulonephritis leading to kidney transplantation), as well as the potential possible but speculative pathogenetic role of acetyl salicylic acid, etc. Primary mucosal and mucocutaneous forms of melanoma remain a challenge for clinicians, and steps for their diagnosis and treatment should be an expression of multidisciplinary, consensual solutions.


Assuntos
Melanoma , Neoplasias Bucais , Neoplasias Cutâneas , Idoso , Humanos , Melanoma/diagnóstico , Melanoma/patologia , Melanoma/terapia , Neoplasias Bucais/patologia , Ácido Micofenólico , Prednisolona , Ácido Salicílico , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Tacrolimo
8.
Genes (Basel) ; 13(10)2022 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-36292642

RESUMO

Melanoma is known as one of the most immunogenic tumours and is often characterised by high mutation burden, neoantigen load and immune infiltrate. The application of immunotherapies has led to impressive improvements in the clinical outcomes of advanced stage melanoma patients. The standard of care immunotherapies leverage the host immunological influence on tumour cells, which entail complex interactions among the tumour, stroma, and immune cells at the tumour microenvironmental level. However, not all cancer patients can achieve a long-term durable response to immunotherapy, and a significant proportion of patients develops resistance and still die from their disease. Owing to the multi-faceted problems of tumour and microenvironmental heterogeneity, identifying the key factors underlying tumour progression and immunotherapy resistance poses a great challenge. In this review, we outline the main challenges to current cancer immunotherapy research posed by tumour heterogeneity and microenvironment complexities including genomic and transcriptomic variability, selective outgrowth of tumour subpopulations, spatial and temporal tumour heterogeneity and the dynamic state of host immunity and microenvironment orchestration. We also highlight the opportunities to dissect tumour heterogeneity using single-cell sequencing and spatial platforms. Integrative analyses of large-scale datasets will enable in-depth exploration of biological questions, which facilitates the clinical application of translational research.


Assuntos
Melanoma , Microambiente Tumoral , Humanos , Microambiente Tumoral/genética , Imunoterapia , Melanoma/genética , Melanoma/terapia , Fatores Imunológicos
9.
J Transl Med ; 20(1): 467, 2022 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-36224560

RESUMO

BACKGROUND: Immunotherapy has dramatically improved cancer treatment by inhibiting or activating specific cell receptors, thus unleashing the host anti-tumor response. However, the engagement of the three main immune checkpoints so far identified, CTLA4, PD-1 and PD-L1, is effective in a fraction of patients, therefore novel targets must be identified and tested. METHODS: We focused our attention on the following nine highly relevant immune checkpoint (ICR) receptors: CTLA4, PD1, PD-L1, LAG3, TIM3, OX40, GITR, 4-1BB and TIGIT. All of them are targets of existing drugs currently under clinical scrutiny in several malignancies. Their expression levels were evaluated in patient tissues of 31 different cancer types vs. proper controls, in a total of 15,038 individuals. This analysis was carried out by interrogating public databases available on GEPIA2 portal and UALCAN portal. By the Principal Component Analysis (PCA) their ability to effectively discriminate patients form controls was then investigated. Expression of the nine ICRs was also related to overall survival in 31 cancer types and expressed as Hazard Ratio, on the GEPIA2 portal and validated, for melanoma patients, in patients-datasets available on PROGgene V2 portal. RESULTS: Significant differential expression was observed for each ICR molecule in many cancer types. A 7-molecules profile was found to specifically discriminate melanoma patients from controls, while two different 6-molecules profiles discriminate pancreatic cancer patients and Testicular Germ Cell Tumors from matched controls. Highly significant survival improvement was found to be related to the expression levels of all nine ICRs in a wide spectrum of malignancies. For melanoma analysis, the relation with survival observed in TCGA datasets was validated in independent GSE melanoma datasets. CONCLUSION: Analysis the nine ICR molecules demonstrates that their expression patterns may be considered as markers of disease and strong survival predictors in a variety of malignancies frequently associated to poor prognosis. Thus, the present findings are strongly advocating that exploratory clinical trials are worth to be performed, using available drugs, targeting these molecules.


Assuntos
Melanoma , Receptor de Morte Celular Programada 1 , Antígeno B7-H1 , Antígeno CTLA-4 , Expressão Gênica , Receptor Celular 2 do Vírus da Hepatite A , Humanos , Fatores Imunológicos , Imunoterapia , Melanoma/genética , Melanoma/terapia , Prognóstico , Receptores Imunológicos
10.
J Transl Med ; 20(1): 489, 2022 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-36303162

RESUMO

RATIONALE: The M2-like tumor-associated macrophages (TAMs) are independent prognostic factors in melanoma. METHODS: We performed weighted gene co-expression network analysis (WGCNA) to identify the module most correlated with M2-like TAMs. The Cancer Genome Atlas (TCGA) patients were classified into two clusters that differed based on prognosis and biological function, with consensus clustering. A prognostic model was established based on the differentially expressed genes (DEGs) of the two clusters. We investigated the difference in immune cell infiltration and immune response-related gene expression between the high and low risk score groups. RESULTS: The risk score was defined as an independent prognostic value in melanoma. VARS1 was a hub gene in the M2-like macrophage-associated WGCNA module that the DepMap portal demonstrated was necessary for melanoma growth. Overexpressing VARS1 in vitro increased melanoma cell migration and invasion, while downregulating VARS1 had the opposite result. VARS1 overexpression promoted M2 macrophage polarization and increased TGF-ß1 concentrations in tumor cell supernatant in vitro. VARS1 expression was inversely correlated with immune-related signaling pathways and the expression of several immune checkpoint genes. In addition, the VARS1 expression level helped predict the response to anti-PD-1 immunotherapy. Pan-cancer analysis demonstrated that VARS1 expression negatively correlated with CD8 T cell infiltration and the immune response-related pathways in most cancers. CONCLUSION: We established an M2-like TAM-related prognostic model for melanoma and explored the role of VARS1 in melanoma progression, M2 macrophage polarization, and the development of immunotherapy resistance.


Assuntos
Melanoma , Macrófagos Associados a Tumor , Humanos , Transcriptoma/genética , Melanoma/genética , Melanoma/terapia , Imunoterapia , Macrófagos/metabolismo , Prognóstico
11.
J Immunother Cancer ; 10(10)2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36192086

RESUMO

BACKGROUND: Current immunotherapies still have limited successful rates among cancers. It is now recognized that T cell functional state in the tumor microenvironment (TME) is a key determinant for effective antitumor immunity and immunotherapy. In addition to exhaustion, cellular senescence in tumor-infiltrating T cells (TILs) has recently been identified as an important T cell dysfunctional state induced by various malignant tumors. Therefore, a better understanding of the molecular mechanism responsible for T cell senescence in the TME and development of novel strategies to prevent effector T cell senescence are urgently needed for cancer immunotherapy. METHODS: Senescent T cell populations in the TMEs in mouse lung cancer, breast cancer, and melanoma tumor models were evaluated. Furthermore, T cell senescence induced by mouse tumor and regulatory T (Treg) cells in vitro was determined with multiple markers and assays, including real-time PCR, flow cytometry, and histochemistry staining. Loss-of-function strategies with pharmacological inhibitors and the knockout mouse model were used to identify the potential molecules and pathways involved in T cell senescence. In addition, melanoma mouse tumor immunotherapy models were performed to explore the synergistical efficacy of antitumor immunity via prevention of tumor-specific T cell senescence combined with anti-programmed death-ligand 1 (anti-PD-L1) checkpoint blockade therapy. RESULTS: We report that both mouse malignant tumor cells and Treg cells can induce responder T cell senescence, similar as shown in human Treg and tumor cells. Accumulated senescent T cells also exist in the TME in tumor models of lung cancer, breast cancer and melanoma. Induction of ataxia-telangiectasia mutated protein (ATM)-associated DNA damage is the cause for T cell senescence induced by both mouse tumor cells and Treg cells, which is also regulated by mitogen-activated protein kinase (MAPK) signaling. Furthermore, blockages of ATM-associated DNA damage and/or MAPK signaling pathways in T cells can prevent T cell senescence mediated by tumor cells and Treg cells in vitro and enhance antitumor immunity and immunotherapy in vivo in adoptive transfer T cell therapy melanoma models. Importantly, prevention of tumor-specific T cell senescence via ATM and/or MAPK signaling inhibition combined with anti-PD-L1 checkpoint blockade can synergistically enhance antitumor immunity and immunotherapy in vivo. CONCLUSIONS: These studies prove the novel concept that targeting both effector T cell senescence and exhaustion is an effective strategy and can synergistically enhance cancer immunotherapy.


Assuntos
Neoplasias da Mama , Imunoterapia , Neoplasias Pulmonares , Melanoma , Linfócitos T , Animais , Neoplasias da Mama/imunologia , Neoplasias da Mama/terapia , Senescência Celular , Feminino , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Melanoma/imunologia , Melanoma/terapia , Camundongos , Proteínas Quinases Ativadas por Mitógeno , Linfócitos T/citologia , Microambiente Tumoral
12.
Front Immunol ; 13: 919145, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36211371

RESUMO

Introduction: Skin cutaneous melanoma (SKCM) is the world's fourth deadliest cancer, and advanced SKCM leads to a poor prognosis. Novel biomarkers for SKCM diagnosis and prognosis are urgently needed. Long non-coding RNAs (lncRNAs) provide various biological functions and have been proved to play a significant role in tumor progression. Single-cell RNA sequencing (scRNA-seq) enables genome analysis at the single-cell level. This study explored prognostic lncRNAs in SKCM based on scRNA-seq and bulk RNA sequencing data. Materials and methods: The TCGA cohort and melanoma samples in the GEO database (GSE72056, GSE19234, GSE15605, GSE7553, and GSE81383) were included in this study. Marker genes were filtered, and ensemble lncRNAs were annotated. The clinical significance of selected lncRNAs was verified through TCGA and GEO dataset analysis. SiRNA transfection, wound-healing and transwell assays were performed to evaluate the effect of PRRT3-AS1 on cellular function. Immune infiltration of the selected lncRNAs was also exhibited. Results: A 5-marker-lncRNAs model of significant prognostic value was constructed based on GSE72056 and the TCGA cohort. PRRT3-AS1 combined with DANCR was then found to provide significant prognostic value in SKCM. PRRT3-AS1 was filtered for its higher expression in more advanced melanoma and significant prognosis value. Cellular function experiments in vitro revealed that PRRT3-AS1 may be required for cancer cell migration in SKCM. PRRT3-AS1 was found to be related to epithelial-mesenchymal transition (EMT) signaling pathways. DNA methylation of PRRT3-AS1 was negatively related to PRRT3-AS1 expression and showed significant prognosis value. In addition, PRRT3-AS1 may suppress immune infiltration and be involved in immunotherapy resistance. Conclusion: PRRT3-AS1 may be a diagnostic and prognostic biomarker of SKCM.


Assuntos
Melanoma , RNA Longo não Codificante , Neoplasias Cutâneas , Biomarcadores , Análise de Dados , Regulação Neoplásica da Expressão Gênica , Humanos , Melanoma/genética , Melanoma/terapia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno
13.
Front Immunol ; 13: 998266, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36248785

RESUMO

Background: The absent in melanoma 2 (AIM2) inflammasome is a multi-protein platform that recognizes aberrant cytoplasmic double-stranded DNA(dsDNA) and induces cytokine maturation, release, and pyroptosis. Some studies found that the AIM2 inflammasome was a double-edged sword in many cancers. However, there have been fewer studies on AIM2 inflammasomes in pan-cancer. Methods: Gene expression was analyzed using The Cancer Genome Atlas (TCGA) database and The Genotype-Tissue Expression (GTEx) database. Immunohistochemistry (IHC) was used to validate the expression of the AIM2. We used the survival curve to explore the prognostic significance of the AIM2 inflammasomes in pan-cancer. Mutations and methylation of AIM2 inflammasome-related genes (AIM2i-RGs) were also comprehensively analyzed. Single sample gene set enrichment analysis was used to calculate the AIM2 inflammasomes score and explore the correlation of the AIM2 inflammasomes score with immune-related genes and immune infiltrations. The function of AIM2 inflammasomes in pan-cancer was analyzed at the single-cell level. Single-cell transcriptome sequencing (scRNA-seq) data was used to assess the activation state of the AIM2 inflammasomes in the tumor microenvironment. Results: We found that AIM2i-RGs were aberrantly expressed in tumors and were strongly associated with prognosis. In pan-cancer, the expression of AIM2i-RGs was positively associated with copy number variation and negatively associated with methylation. In AIM2i-RGs, missense mutations were the predominant type of single nucleotide polymorphism. Moreover, we found that the drugs dimethyloxallyl glycine (DMOG) and Z-LNle-CHO may be sensitive to the AIM2 inflammasomes. The AIM2 inflammasomes score was significantly and positively correlated with the tumor immunity score and the stroma score. In most tumors, the AIM2 inflammasomes score was significantly and positively correlated with CD8+ T cell abundance in the tumor microenvironment. Additionally, the AIM2 inflammasomes score was significantly correlated with immune checkpoint genes in pan-cancer as well as immune checkpoint therapy-related markers including tumor mutational burden (TMB), microsatellite instability(MSI), and tumor immune dysfunction and exclusion(TIDE). scRNA-seq analysis suggested that AIM2 inflammasomes differ significantly among different cells in the tumor microenvironment. IHC confirmed low expression of AIM2 in colorectal cancer. Discussion: AIM2 inflammasomes may be a new target for future tumor therapy It is likely involved in tumor development, and its high expression may serve as a predictor of tumor immunotherapy efficacy.


Assuntos
Inflamassomos , Melanoma , Citocinas/genética , DNA , Variações do Número de Cópias de DNA , Proteínas de Ligação a DNA/metabolismo , Humanos , Fatores Imunológicos , Imunoterapia , Inflamassomos/metabolismo , Melanoma/genética , Melanoma/terapia , Microambiente Tumoral/genética
14.
Med (N Y) ; 3(10): 645-647, 2022 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-36242997

RESUMO

Tumor-infiltrating lymphocytes show consistent clinical benefit in metastatic melanoma, but they are a poorly defined product with variable antitumor activity. In this issue, Palmer et al.1 create for clinical testing a cell product consisting of highly functional tumor-reactive T cells by knocking out CISH, an inhibitor of T cell activation.


Assuntos
Linfócitos do Interstício Tumoral , Melanoma , Humanos , Ativação Linfocitária , Melanoma/terapia , Linfócitos T/patologia
15.
BMC Cancer ; 22(1): 1041, 2022 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-36199130

RESUMO

BACKGROUND: Adjuvant therapies such as radiation therapy, chemotherapy, and immunotherapy are usually given after cancer surgery to improve the survival of cancer patients. However, despite advances in several adjuvant therapies, they are still limited in the prevention of recurrences. METHODS: We evaluated the immunological effects of RNA-based adjuvants in a murine melanoma model. Single-stranded RNA (ssRNA) were constructed based on the cricket paralysis virus (CrPV) internal ribosome entry site (IRES). Populations of immune cells in bone marrow cells and lymph node cells following immunization with CrPVIRES-ssRNA were determined using flow cytometry. Activated cytokine levels were measured using ELISA and ELISpot. The tumor protection efficacy of CrPVIRES-ssRNA was analyzed based on any reduction in tumor size or weight, and overall survival. RESULTS: CrPVIRES-ssRNA treatment stimulated antigen-presenting cells in the drain lymph nodes associated with activated antigen-specific dendritic cells. Next, we evaluated the expression of CD40, CD86, and XCR1, showing that immunization with CrPVIRES-ssRNA enhanced antigen presentation by CD8a+ conventional dendritic cell 1 (cDC1), as well as activated antigen-specific CD8 T cells. In addition, CrPVIRES-ssRNA treatment markedly increased the frequency of antigen-specific CD8 T cells and interferon-gamma (IFN-γ) producing cells, which promoted immune responses and reduced tumor burden in melanoma-bearing mice. CONCLUSIONS: This study provides evidence that the CrPVIRES-ssRNA adjuvant has potential for use in therapeutic cancer vaccines. Moreover, CrPVIRES-ssRNA possesses protective effects on various cancer cell models.


Assuntos
Vacinas Anticâncer , Melanoma , Adjuvantes Imunológicos , Animais , Vacinas Anticâncer/uso terapêutico , Imunoterapia , Interferon gama/genética , Sítios Internos de Entrada Ribossomal , Melanoma/genética , Melanoma/terapia , Camundongos , RNA Viral/genética
16.
Eur J Dermatol ; 31(4): 521-529, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-36094385

RESUMO

Background: The COVID-19 pandemic imposes major challenges for care of cancer patients. Objectives: Our aim was to assess the effects of the pandemic on treatment and appointments of patients with malignant melanoma based on a large skin cancer centre in Berlin, Germany, and identify reasons for, and impact factors associated with these changes. Materials & Methods: Patients with melanoma treated from January 1st 2019 received a postal survey with questions on impairment due to the pandemic, fear of COVID-19, fear of melanoma, changes in therapy and/or appointments, including reasons for the changes. Impact factors on postponed/missed appointments were examined using descriptive analyses and multivariate logistic regression. Results: The response rate was 41.3% (n = 324; 57.4% males; mean age: 67.9 years). Among 104 participants currently receiving therapy, four (3.8%) reported treatment changes due to the pandemic. Postponements or cancellations of appointments occurred in 48 participants (14.8%), most frequently, at their own request (81.3%) due to fear of SARS-CoV-2 infection (68.8%). Current treatment was associated with a reduced chance of post-poning/missing appointments (OR = 0.208, p = 0.003), whereas a high or very high level of concern for COVID-19 (OR = 6.806, p = 0.034; OR= 10.097, p = 0.038), SARS-CoV-2 infection among close acquaintances (OR = 4.251, p = 0.026), anxiety disorder (OR = 5.465, p = 0.016) and AJCC stage IV (OR = 3.108, p = 0.048) were associated with a higher likelihood of postponing/missing appointments. Conclusion: Among our participants, treatment changes were rare and the proportion of missed/delayed appointments was rather small. The main reasons for delays/cancellations of appointments were anxiety and concern for COVID-19.


Assuntos
COVID-19 , Melanoma , Idoso , Berlim , Feminino , Alemanha/epidemiologia , Humanos , Masculino , Melanoma/epidemiologia , Melanoma/terapia , Pandemias , SARS-CoV-2
17.
Stem Cells Dev ; 31(19-20): 593-603, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36066334

RESUMO

Adipose-derived stromal cells (ADSCs) have well-established regenerative and immunomodulatory properties. For such reasons, ADSCs are currently under investigation for their use in the setting of both regenerative medicine and autoimmune diseases. As per dermatological disorders, mesenchymal stromal cell (MSC)-based strategies represent potential therapeutic tools not only for chronic ulcers and wound healing, but also for immune-mediated dermatoses. However, a growing body of research has been focusing on the role of MSCs in human cancers, due to the potential oncological risk of using MSC-based strategies linked to their antiapoptotic, proangiogenic, and immunosuppressive properties. In the dermatological setting, ADSCs have shown not only to promote melanoma growth and invasiveness, but also to induce drug resistance. In contrast, genetically modified ADSCs have been demonstrated to efficiently target therapies at tumor sites, due to their migratory properties and their peculiar tropism for cancer microenvironment. The present review briefly summarizes the findings published so far on the use of ADSCs in the dermato-oncological setting, with the majority of data being available for melanoma.


Assuntos
Melanoma , Células-Tronco Mesenquimais , Humanos , Motivação , Tecido Adiposo , Medicina Regenerativa , Melanoma/terapia , Microambiente Tumoral
18.
Dermatol Ther ; 35(11): e15817, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36093750

RESUMO

Adjuvant nivolumab therapy has been reported to improve the survival of melanoma patients. Acral lentiginous melanoma (ALM) has been reported to be less likely to respond to immune checkpoint inhibitors (ICIs) than other subtypes. However, the efficacy of adjuvant nivolumab therapy for ALM patients remains uncertain due to the low number of cases. In this single-center retrospective case series, we analyzed the clinical data of patients with resected stage III/IV ALM who were referred to our department between April 1, 2004 and March 31, 2022. The analyzed clinical data included age, sex, TNM stage, treatments, adverse events and disease-free survival (DFS). Enrolled patients were divided into a nivolumab group and a non-ICI group according to the adjuvant therapy they received. In total, 27 patients were included. The nivolumab and non-ICI groups had 5 and 22 patients, respectively. There were no significant differences in patient characteristics between the two groups. There were no serious treatment-related adverse events in the non-ICI group, but one patient in the nivolumab group developed type 1 diabetes. In the survival analysis, the DFS for the nivolumab group did not exceed that of the non-ICI group in postoperative adjuvant therapy for ALM patients. Given that adjuvant nivolumab therapy sometimes results in serious adverse effects, the administration of the therapy may need to be carefully considered, especially for ALM patients.


Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Nivolumabe/efeitos adversos , Intervalo Livre de Doença , Estudos Retrospectivos , Melanoma/terapia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/cirurgia
19.
Adv Med Sci ; 67(2): 364-378, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36155341

RESUMO

PURPOSE: Although skin cutaneous melanoma (SKCM) is a relatively immunotherapy-sensitive tumor type, there is still a certain fraction that benefits less from treatment. Ferroptosis has been demonstrated to modulate tumor progression in many cancer types. This study focused on ferroptosis-related genes to construct a prognostic model for SKCM patients. MATERIALS AND METHODS: Gene expression profiles of SKCM samples were obtained from public databases. Unsupervised consensus clustering was used to determine molecular subtypes related to ferroptosis. Least absolute shrinkage and selection operator (LASSO) and stepwise Akaike information criterion (stepAIC) were applied to construct a prognostic model based on differentially expressed genes between two molecular subtypes. RESULTS: C1 and C2 subtypes were identified with differential prognosis and immune infiltration. A 7-gene prognostic model was constructed to classify samples into high-FPRS and low-FPRS groups. Low-FPRS group with favorable prognosis had higher immune infiltration and more enriched immune-related pathways than the high-FPRS group. The two groups showed distinct sensitivity to immunotherapy, with the low-FPRS group predicted to have more positive response to immunotherapy than the high-FPRS group. A nomogram based on the FPRS score and clinical features was built for more convenient use. CONCLUSIONS: The critical role of ferroptosis involved in SKCM development was further validated in this study. The prognostic model was efficient and stable to be applied in clinical conditions to support clinicians in determining personalized therapy for SKCM patients especially those with metastasis.


Assuntos
Ferroptose , Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/genética , Melanoma/terapia , Melanoma/metabolismo , Prognóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/terapia , Neoplasias Cutâneas/metabolismo , Ferroptose/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Imunoterapia
20.
Adv Med Sci ; 67(2): 338-345, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36084365

RESUMO

PURPOSE: Melanoma is a malignant and metastatic form of skin cancer, which is not diagnosed in early stages of the disease. Nowadays, immunotherapy is changing the treatment landscape for metastatic melanoma. Placenta-specific1 (PLAC1) is a cancer-testis-placenta (CTP) antigen with differential expression in melanoma tissues. Here, we evaluated the potential of plac1 to induce anti-cancer immune responses as well as to prevent cancer development in a mouse model of melanoma. METHODS: Two proteins containing full extracellular domain (ED) of mouse plac1+KDEL3 and full ED of mouse plac1+ tetanus toxin P2 and P30+ pan DR epitope (PADRE) â€‹+ â€‹KDEL3 were produced and injected in mice to evaluate their capacity to induce anti-cancer immune responses as well as their potential to prevent melanoma development. Induction of plac1-specific humoral and cellular responses as well as tumor-associated parameters were tested in a series of 36 mice. RESULTS: Sera of mice immunized with ED â€‹+ â€‹P2P30+PADRE â€‹+ â€‹KDEL3 contained antibodies able to react with surface plac1 in B16F10 â€‹cells. Both proteins induced proliferative cellular immune responses against B16F10 â€‹cells and plac1-specific cytotoxic T cells (CTL) and CD107a â€‹+ â€‹CTL responses, which was higher in mice immunized with ED â€‹+ â€‹P2P30+PADRE â€‹+ â€‹KDEL3. Splenocytes of mice vaccinated with ED â€‹+ â€‹P2P30+PADRE â€‹+ â€‹KDEL3 exerted a significant cytotoxicity against B16F10 â€‹cells. Vaccination with ED â€‹+ â€‹P2P30+PADRE â€‹+ â€‹KDEL3 significantly delayed B16F10-induced tumor onset, reduced tumor growth, and increased survival. Tumors induced by B16F10 expressed plac1 in vivo. CONCLUSION: Our results pave the way for development of effective melanoma preventive vaccine in humans, although further studies are needed.


Assuntos
Vacinas Anticâncer , Melanoma , Proteínas da Gravidez , Masculino , Camundongos , Humanos , Animais , Toxina Tetânica , Citidina Trifosfato , Imunização , Vacinação , Modelos Animais de Doenças , Melanoma/terapia , Epitopos
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