Asunto(s)

Anticuerpos Monoclonales Humanizados , Antineoplásicos Inmunológicos , Encefalitis , Melanoma , Humanos , Femenino , Melanoma/tratamiento farmacológico , Melanoma/secundario , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Encefalitis/inducido químicamente , Encefalitis/diagnóstico , Antineoplásicos Inmunológicos/efectos adversos , Neoplasias Cutáneas , Enfermedad de Hashimoto/complicaciones , Persona de Mediana Edad

RESUMEN

Melanoma either intrinsically possesses resistance or rapidly acquires resistance to anti-tumor therapy, which often leads to local recurrence or distant metastasis after resection. In this study, we found histone 3 lysine 27 (H3K27) demethylated by an inhibitor of histone methyltransferase EZH2 could epigenetically reverse the resistance to chemo-drug paclitaxel (PTX), or enhance the efficacy of immune checkpoint inhibitor anti-TIGIT via downregulating TIGIT ligand CD155. Next, to address the complexity in the combination of multiple bioactive molecules with distinct therapeutic properties, we developed a polysaccharides-based organohydrogel (OHG) configured with a heterogenous network. Therein, hydroxypropyl chitosan (HPC)-stabilized emulsions for hydrophobic drug entrapment were crosslinked with oxidized dextran (Odex) to form a hydrophilic gel matrix to facilitate antibody accommodation, which demonstrated a tunable sustained release profile by optimizing emulsion/gel volume ratios. As results, local injection of OHG loaded with EZH2 inhibitor UNC1999, PTX and anti-TIGIT did not only synergistically enhance the cytotoxicity of PTX, but also reprogrammed the immune resistance via bi-directionally blocking TIGIT/CD155 axis, leading to the recruitment of cytotoxic effector cells into tumor and conferring a systemic immune memory to prevent lung metastasis. Hence, this polysaccharides-based OHG represents a potential in-situ epigenetic-, chemo- and immunotherapy platform to treat unresectable metastatic melanoma.

Asunto(s)

Quitosano , Dextranos , Proteína Potenciadora del Homólogo Zeste 2 , Epigénesis Genética , Melanoma , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/inmunología , Quitosano/química , Quitosano/análogos & derivados , Dextranos/química , Animales , Melanoma/tratamiento farmacológico , Melanoma/patología , Melanoma/inmunología , Ratones , Humanos , Epigénesis Genética/efectos de los fármacos , Paclitaxel/farmacología , Paclitaxel/química , Paclitaxel/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Hidrogeles/química , Línea Celular Tumoral , Receptores Inmunológicos/antagonistas & inhibidores , Receptores Inmunológicos/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química

RESUMEN

BACKGROUND: Following major achievements seen with drug therapies for the treatment of advanced melanoma in the last decade, they now also have an ever-increasing role for the treatment of earlier stage disease. This review outlines the current drugs used to treat melanoma, and how general practitioners (GPs) can assist in the management of patients with melanoma and the associated toxicities with treatment. OBJECTIVE: This review summarises the evolving status of melanoma care, emphasising when to refer patients to medical oncologists as part of the multidisciplinary team. It provides guidance into recognising and managing immune-related adverse events (irAEs) associated with immunotherapy, and provides insights into the future changes in clinical practice. DISCUSSION: Drug therapies are increasingly used for the treatment of many patients with melanoma. Early referral is crucial, and clinical trials remain the best choice for most patients. Recognition and prompt management of irAEs is vital, and collaboration between GPs and oncologists is essential for best care.

Asunto(s)

Médicos Generales , Melanoma , Humanos , Melanoma/tratamiento farmacológico , Médicos Generales/tendencias , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversos , Rol del Médico

RESUMEN

Neoantigen-based immunotherapy is an attractive potential treatment for previously intractable tumors. To effectively broaden the application of this approach, stringent biomarkers are crucial to identify responsive patients. ARID1A, a frequently mutated subunit of SWI/SNF chromatin remodeling complex, has been reported to determine tumor immunogenicity in some cohorts; however, mutations and deletions of ARID1A are not always linked to clinical responses to immunotherapy. In this study, we investigated immunotherapeutic responses based on ARID1A status in targeted therapy-resistant cancers. Mouse and human BRAFV600E melanomas with or without ARID1A expression were transformed into resistant to vemurafenib, an FDA-approved specific BRAFV600E inhibitor. Anti-PD-1 antibody treatment enhanced antitumor immune responses in vemurafenib-resistant ARID1A-deficient tumors but not in ARID1A-intact tumors or vemurafenib-sensitive ARID1A-deficient tumors. Neoantigens derived from accumulated somatic mutations during vemurafenib resistance were highly expressed in ARID1A-deficient tumors and promoted tumor immunogenicity. Furthermore, the newly generated neoantigens could be utilized as immunotherapeutic targets by vaccines. Finally, targeted therapy resistance-specific neoantigen in experimental human melanoma cells lacking ARID1A were validated to elicit T-cell receptor responses. Collectively, the classification of ARID1A-mutated tumors based on vemurafenib resistance as an additional indicator of immunotherapy response will enable a more accurate prediction to guide cancer treatment. Furthermore, the neoantigens that emerge with therapy resistance can be promising therapeutic targets for refractory tumors. Significance: Chemotherapy resistance promotes the acquisition of immunogenic neoantigens in ARID1A-deficient tumors that confer sensitivity to immune checkpoint blockade and can be utilized for developing antitumor vaccines, providing strategies to improve immunotherapy efficacy.

Asunto(s)

Antígenos de Neoplasias , Proteínas de Unión al ADN , Resistencia a Antineoplásicos , Melanoma , Factores de Transcripción , Vemurafenib , Animales , Humanos , Factores de Transcripción/genética , Factores de Transcripción/inmunología , Ratones , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/inmunología , Resistencia a Antineoplásicos/inmunología , Antígenos de Neoplasias/inmunología , Antígenos de Neoplasias/genética , Vemurafenib/farmacología , Vemurafenib/uso terapéutico , Melanoma/inmunología , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/terapia , Inmunoterapia/métodos , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/inmunología , Línea Celular Tumoral , Femenino , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Mutación , Terapia Molecular Dirigida/métodos , Ratones Endogámicos C57BL

RESUMEN

Extracellular adenosine is extensively involved in regulating the tumor microenvironment. Given the disappointing results of adenosine-targeted therapy trials, personalized treatment might be necessary, tailored to the microenvironment status of individual patients. Here, we introduce the adenosine signaling score (ADO-score) model using non-negative matrix fraction identified patient subtypes using publicly available melanoma dataset, which aimed to profile adenosine signaling-related genes and construct a model to predict prognosis. We analyzed 580 malignant melanoma samples and demonstrated its robust value for prognosis. Further investigation in immune checkpoint inhibitor dataset suggests its potential as a stratified factor of immune checkpoint inhibitor efficacy. We validated the power of the ADO-score at the protein level immunofluorescence in a melanoma cohort from Xiangya Hospital. More importantly, single-cell and spatial transcriptomic data highlighted the cell-specific expression patterns of adenosine signaling-related genes and the existence of adenosine signaling-mediated crosstalk between tumor cells and immune cells in melanoma. Our study reveals a robust connection between adenosine signaling and clinical benefits in melanoma patients and proposes a universally applicable adenosine signaling model, the ADO-score, in gene expression profiles and histological sections. This model enables us to more precisely and conveniently select patients who are likely to benefit from immunotherapy.

Asunto(s)

Adenosina , Inmunoterapia , Melanoma , Transducción de Señal , Microambiente Tumoral , Humanos , Melanoma/genética , Melanoma/patología , Melanoma/inmunología , Melanoma/tratamiento farmacológico , Adenosina/metabolismo , Adenosina/genética , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Transducción de Señal/genética , Pronóstico , Regulación Neoplásica de la Expresión Génica/genética , Transcriptoma/genética , Perfilación de la Expresión Génica , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Femenino , Masculino , Multiómica

RESUMEN

Mucosal melanoma (MM) poses a significant clinical challenge due to its aggressive nature and limited treatment options. In recent years, immunotherapy has emerged as a promising strategy for MM, with a particular focus on immune checkpoint inhibitors such as PD-1 and CTLA-4 inhibitors. These inhibitors have demonstrated substantial efficacy by harnessing the body's immune response against tumors. Moreover, adoptive cell transfer (ACT), anti-angiogenic therapy, and combination therapies have garnered attention for their potential in MM treatment. ACT involves modifying T cells to target melanoma cells, showing promising antitumor activity. Anti-angiogenic therapy aims to impede tumor growth by inhibiting angiogenesis, while combination therapies, including immune checkpoint inhibitors and targeted therapies, offer a multifaceted approach to overcome treatment resistance. This comprehensive review explores the advancements in immunotherapy for MM, highlighting the role of diverse therapeutic modalities in enhancing treatment outcomes and addressing the challenges posed by this aggressive malignancy.

Asunto(s)

Inhibidores de Puntos de Control Inmunológico , Inmunoterapia , Melanoma , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Melanoma/terapia , Melanoma/inmunología , Melanoma/tratamiento farmacológico , Inmunoterapia/métodos , Animales , Resultado del Tratamiento , Membrana Mucosa/inmunología , Terapia Combinada , Inmunoterapia Adoptiva/métodos

RESUMEN

Introduction: The role of zinc (Zn) in tumor development and immune modulation has always been paradoxical. This study redefines our understanding of the impact of Zn on cancer progression and therapeutic strategies. Methods: We investigated the effects of dietary Zn levels on tumor progression and immune responses. This included examining the impact of both high and deficient dietary Zn, as well as Zn chelation, on tumor growth and immune cell populations. Specifically, we analyzed the frequency of Foxp3+ regulatory T-cells (Tregs) and identified the role of FOXO1 in Zn-mediated effects on Tregs. Additionally, we explored the therapeutic potential of clioquinol (CQ) in enhancing α-PD-1 immunotherapy responses, particularly in melanoma. Results: Our findings show that high dietary Zn promotes tumor progression by fostering a protumorigenic environment mediated by T cells. Increased Zn intake was found to facilitate tumor progression by increasing Foxp3+ Treg frequency. In contrast, deficiency in dietary Zn and chelation of tissue Zn emerged as potent drivers of antitumor immunity. We pinpointed FOXO1 as the master regulator governing the influence of Zn on Tregs. Discussion: These results reveal a novel mechanistic insight into how Zn influences tumor progression and immune regulation. The identification of FOXO1 as a key regulator opens new avenues for understanding the role of Zn in cancer biology. Furthermore, we introduce a promising therapeutic approach by showing that administering clioquinol (CQ) significantly enhances α-PD-1 immunotherapy response, particularly in melanoma. These revelations transform our comprehension of the multifaceted role of Zn in tumorigenesis and immune regulation, highlighting innovative possibilities for cancer therapy.

Asunto(s)

Factores de Transcripción Forkhead , Linfocitos T Reguladores , Zinc , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Animales , Zinc/metabolismo , Factores de Transcripción Forkhead/metabolismo , Ratones , Clioquinol/farmacología , Ratones Endogámicos C57BL , Proteína Forkhead Box O1/metabolismo , Proteína Forkhead Box O1/genética , Melanoma Experimental/inmunología , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/metabolismo , Melanoma/inmunología , Melanoma/tratamiento farmacológico , Humanos , Línea Celular Tumoral , Microambiente Tumoral/inmunología , Microambiente Tumoral/efectos de los fármacos , Inmunoterapia/métodos , Femenino

RESUMEN

Cutaneous melanoma is an aggressive type of skin cancer that is recognized for its high metastatic potential and the challenges it presents in its treatment. There has been increasing interest in plant extracts and their potential applications in melanoma. The present study aimed to investigate the content of individual phenolic compounds in araçá-boi extract, evaluate their antioxidant activity, and explore their effects on cell viability, migration properties, oxidative stress levels, and protein expression in the human metastatic melanoma cell line SK-MEL-28. HPLC-DAD analysis identified 11 phenolic compounds in the araçá-boi extract. Trans-cinnamic acid was the main phenolic compound identified; therefore, it was used alone to verify its contribution to antitumor activities. SK-MEL-28 melanoma cells were treated for 24 h with different concentrations of araçá-boi extract and trans-cinnamic acid (200, 400, 600, 800, and 1600 µg/mL). Both the araçá-boi extract and trans-cinnamic acid reduced cell viability, cell migration, and oxidative stress in melanoma cells. Additionally, they modulate proteins involved in apoptosis and inflammation. These findings suggest the therapeutic potential of araçá-boi extract and its phenolic compounds in the context of melanoma, especially in strategies focused on preventing metastasis. Additional studies, such as the analysis of specific signaling pathways, would be valuable in confirming and expanding these observations.

Asunto(s)

Movimiento Celular , Supervivencia Celular , Cinamatos , Melanoma , Fenoles , Extractos Vegetales , Humanos , Melanoma/tratamiento farmacológico , Melanoma/patología , Melanoma/metabolismo , Movimiento Celular/efectos de los fármacos , Extractos Vegetales/farmacología , Supervivencia Celular/efectos de los fármacos , Cinamatos/farmacología , Línea Celular Tumoral , Fenoles/farmacología , Antioxidantes/farmacología , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Estrés Oxidativo/efectos de los fármacos , Apoptosis/efectos de los fármacos , Antineoplásicos Fitogénicos/farmacología

RESUMEN

BACKGROUND: Immunotherapies for malignant melanoma are challenged by the resistance developed in a significant proportion of patients. Myeloid-derived suppressor cells (MDSC), with their ability to inhibit antitumor T-cell responses, are a major contributor to immunosuppression and resistance to immune checkpoint therapies in melanoma. Damage-associated molecular patterns S100A8, S100A9, and HMGB1, acting as toll like receptor 4 (TLR4) and receptor for advanced glycation endproducts (RAGE) ligands, are highly expressed in the tumor microenvironment and drive MDSC activation. However, the role of TLR4 and RAGE signaling in the acquisition of MDSC immunosuppressive properties remains to be better defined. Our study investigates how the signaling via TLR4 and RAGE as well as their ligands S100A9 and HMGB1, shape MDSC-mediated immunosuppression in melanoma. METHODS: MDSC were isolated from the peripheral blood of patients with advanced melanoma or generated in vitro from healthy donor-derived monocytes. Monocytes were treated with S100A9 or HMGB1 for 72 hours. The immunosuppressive capacity of treated monocytes was assessed in the inhibition of T-cell proliferation assay in the presence or absence of TLR4 and RAGE inhibitors. Plasma levels of S100A8/9 and HMGB1 were quantified by ELISA. Single-cell RNA sequencing (scRNA-seq) was performed on monocytes from patients with melanoma and healthy donors. RESULTS: We showed that exposure to S100A9 and HMGB1 converted healthy donor-derived monocytes into MDSC through TLR4 signaling. Our scRNA-seq data revealed in patient monocytes enriched inflammatory genes, including S100 and those involved in NF-κB and TLR4 signaling, and a reduced major histocompatibility complex II gene expression. Furthermore, elevated plasma S100A8/9 levels correlated with shorter progression-free survival in patients with melanoma. CONCLUSIONS: These findings highlight the critical role of TLR4 and, to a lesser extent, RAGE signaling in the conversion of monocytes into MDSC-like cells, underscore the potential of targeting S100A9 to prevent this conversion, and highlight the prognostic value of S100A8/9 as a plasma biomarker in melanoma.

Asunto(s)

Calgranulina B , Proteína HMGB1 , Melanoma , Células Supresoras de Origen Mieloide , Transducción de Señal , Receptor Toll-Like 4 , Humanos , Calgranulina B/metabolismo , Receptor Toll-Like 4/metabolismo , Proteína HMGB1/metabolismo , Melanoma/inmunología , Melanoma/metabolismo , Melanoma/tratamiento farmacológico , Células Supresoras de Origen Mieloide/metabolismo , Células Supresoras de Origen Mieloide/inmunología , Masculino , Femenino , Microambiente Tumoral/inmunología , Persona de Mediana Edad , Tolerancia Inmunológica

RESUMEN

Resistance biomarkers are needed to identify patients with advanced melanoma obtaining a response to ICI treatment and developing resistance later. We searched a combination of molecular signatures of response to ICIs in patients with metastatic melanoma. In a retrospective study on patients with metastatic melanoma treated with an anti-PD-1 agent carried out at Istituto Nazionale Tumori-IRCCS-Fondazione "G. Pascale", Naples, Italy. We integrated a whole proteome profiling of metastatic tissue with targeted transcriptomics. To assess the prognosis of patients according to groups of low and high risk, we used PFS and OS as outcomes. To identify the proteins and mRNAs gene signatures associated with the patient's response groups, the discriminant analysis for sparse data performed via partial least squares procedure was performed. Tissue samples from 22 patients were analyzed. A combined protein and gene signature associated with poorer response to ICI immunotherapy in terms of PFS and OS was identified. The PFS and OS Kaplan-Meier curves were significantly better for patients with high expression of the protein signature compared to patients with low expression of the protein signature and who were high-risk (Protein: HR = 0.023, 95% CI: 0.003-0.213; p < 0.0001. Gene: HR = 0.053, 95% CI: 0.011-0.260; p < 0.0001). The Kaplan-Meier curves showed that patients with low-risk gene signatures had better PFS (HR = 0 0.221, 95% CI: 0.071-0.68; p = 0.007) and OS (HR = 0.186, 95% CI: 0.05-0.695; p = 0.005). The proteomic and transcriptomic combined analysis was significantly associated with the outcomes of the anti-PD-1 treatment with a better predictive value compared to a single signature. All the patients with low expression of protein and gene signatures had progression within 6 months of treatment (median PFS = 3 months, 95% CI: 2-3), with a significant difference vs. the low-risk group (median PFS = not reached; p < 0.0001), and significantly poorer survival (OS = 9 months, 95% CI: 5-9) compared to patients with high expression of protein and gene signatures (median OS = not reached; p < 0.0001). We propose a combined proteomic and transcriptomic signature, including genes involved in pro-tumorigenic pathways, thereby identifying patients with reduced probability of response to immunotherapy with ICIs for metastatic melanoma.

Asunto(s)

Inhibidores de Puntos de Control Inmunológico , Melanoma , Proteómica , Transcriptoma , Humanos , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/patología , Melanoma/metabolismo , Melanoma/mortalidad , Femenino , Masculino , Estudios Retrospectivos , Proteómica/métodos , Persona de Mediana Edad , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Anciano , Pronóstico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/genética , Biomarcadores de Tumor/genética , Adulto , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Proteoma/metabolismo , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/metabolismo , Metástasis de la Neoplasia

RESUMEN

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.

Asunto(s)

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 Tratamiento

RESUMEN

Melanoma is a malignant skin cancer associated with high mortality rates and drug resistance, posing a significant threat to human health. The combination of chemotherapy and photodynamic therapy (PDT) represents a promising strategy to enhance antitumor efficacy through synergistic anti-cancer effects. Topical delivery of chemotherapeutic drugs and photosensitizers (PS) offers a non-invasive and safe way to treat melanoma. However, the effectiveness of these treatments is often hindered by challenges such as limited skin permeability and instability of the PS. In this study, transfersomes (TFS) were designed to facilitate transdermal delivery of the chemotherapeutic drug 5-Fluorouracil (5-FU) and the PS Imperatorin (IMP) for combined chemo-photodynamic therapy for melanoma. The cytotoxic and phototoxic effects of TFS-mediated PDT (TFS-UVA) were investigated in A375 cells and nude mice. The study also demonstrated that TFS-UVA generated intracellular ROS, induced G2/ M phase cell cycle arrest, and promoted cell apoptosis. In conclusion, this study indicated that 5-FU/ IMP-TFS serves as an effective transdermal therapeutic strategy for chemo-PDT in treating melanoma.

Asunto(s)

Apoptosis , Puntos de Control del Ciclo Celular , Fluorouracilo , Melanoma , Fotoquimioterapia , Fármacos Fotosensibilizantes , Fotoquimioterapia/métodos , Animales , Humanos , Apoptosis/efectos de los fármacos , Melanoma/tratamiento farmacológico , Melanoma/patología , Ratones , Fluorouracilo/farmacología , Fluorouracilo/administración & dosificación , Línea Celular Tumoral , Puntos de Control del Ciclo Celular/efectos de los fármacos , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/administración & dosificación , Ratones Desnudos , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Especies Reactivas de Oxígeno/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Administración Tópica , Furocumarinas/farmacología , Furocumarinas/administración & dosificación , Furocumarinas/química

RESUMEN

Despite unquestionable advances in therapy, melanoma is still characterized by a high mortality rate. For years, high expectations have been raised by compounds of natural origin as a component of pharmacotherapy, particularly by triterpenes found in the bark of birch trees. In this study, 3,4-seco-dammara-4(29),20(21),24(25)-trien-3-oic acid (SDT) was isolated from buds of silver birch and its mechanisms of cell death induction, including apoptosis and autophagy, were determined. Cytotoxicity of SDT was evaluated by the cell viability test and clonogenic assay, whereas induction of apoptosis and autophagy was determined by annexin V staining and Western blot. The results revealed dose- and time-dependent reductions in viability of melanoma cells. Treatment of cells for 48 h led to an increase in the percentage of annexin V-positive cells, activation of caspase-8, caspase-9, and caspase-3, and cleavage of PARP, confirming apoptosis. Simultaneously, it was found that SDT increased the level of autophagy marker LC3-II and initiator of autophagy beclin-1. Pretreatment of cells with caspase-3 inhibitor or autophagy inhibitor significantly reduced the cytotoxicity of SDT and revealed that both apoptosis and autophagy contribute to a decrease in cell viability. These findings suggest that 3,4-seco-dammaranes may become a promising group of natural compounds for searching for anti-melanoma agents.

Asunto(s)

Apoptosis , Autofagia , Betula , Melanoma , Triterpenos , Humanos , Triterpenos/farmacología , Triterpenos/química , Autofagia/efectos de los fármacos , Apoptosis/efectos de los fármacos , Betula/química , Melanoma/tratamiento farmacológico , Melanoma/patología , Melanoma/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Extractos Vegetales/farmacología , Extractos Vegetales/química

RESUMEN

Squalene (SQ) is a well-known antioxidant and anti-inflammatory agent that provides promising anti-aging and UV-protective roles on human skin. However, its strong hydrophobic nature, accompanied by issues such as poor solubility and limited tissue permeation, has created challenges for scientists to investigate its untapped potential in more complex conditions, including cancer progression. The present study assessed the potent anti-metastatic properties of a newly synthesized amphiphilic ethylene glycol SQ derivative (SQ-diEG) in melanoma, the most fatal skin cancer. In vitro and in vivo experiments have discovered that SQ-diEG may exert its potential on melanoma malignancy through the mitochondria-mediated caspase activation apoptotic signaling pathway. The potent anti-metastatic effect of SQ-diEG was observed in vitro using highly proliferative and aggressive melanoma cells. Administration of SQ-diEG (25 mg/kg) significantly decreased the tumor burden on the lung and inhibited the metastasis-associated proteins and gene markers in B16F10 lung colonization mice model. Furthermore, global gene profiling also revealed a promising role of SQ-diEG in tumor microenvironment. We anticipated that the amphiphilic nature of the SQ compound bearing ethylene glycol oligomers could potentially augment its ability to reach the pathology site, thus enhancing its therapeutic potential in melanoma.

Asunto(s)

Melanoma , Escualeno , Animales , Ratones , Escualeno/química , Escualeno/farmacología , Humanos , Línea Celular Tumoral , Melanoma/patología , Melanoma/tratamiento farmacológico , Ratones Endogámicos C57BL , Apoptosis/efectos de los fármacos , Melanoma Experimental/patología , Melanoma Experimental/tratamiento farmacológico , Metástasis de la Neoplasia , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Éteres/farmacología , Éteres/química , Proliferación Celular/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/tratamiento farmacológico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos/química

RESUMEN

Combination immunotherapy improves outcomes in metastatic melanoma, but the underlying mechanisms remain unclear. In this issue of Cancer Cell, Wang et al.1 report dynamics and transcriptional states of CD8+ T cell clones over time in patients treated with anti-PD-1, anti-CTLA-4, or a combination of the two. These findings have important implications for understanding and monitoring combination immunotherapy.

Asunto(s)

Linfocitos T CD8-positivos , Inmunoterapia , Melanoma , Humanos , Inmunoterapia/métodos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Melanoma/inmunología , Melanoma/terapia , Melanoma/tratamiento farmacológico , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología

RESUMEN

Uveal melanoma (UM) is the most prevalent type of primary intraocular malignancy and is prone to metastasize, particularly to the liver. However, due to the poor understanding of the pathogenesis of UM, effective therapeutic approaches are lacking. As a phenolic compound extracted from grapes, piceatannol (PIC) exhibits anti­cancer properties. To the best of our knowledge, however, the effects of PIC on UM have not been well investigated. Therefore, in the present study, considering the impact of pyroptosis on modulating cell viability, the mechanism underlying the effects of PIC on UM cell proliferation was explored. The inhibitory effect of PIC on proliferation of UM cells was detected by cell counting kit­8 assay. Wound healing was used to investigate the effects of PIC on the migration of UM cells. Activity detecting assays were performed to test the apoptosis and oxidant level in UM cells. Western blotting and RT­qPCR were used to detect the inflammatory and pyroptotic levels of UM cell after PIC treatment. PIC­treated UM cells were screened by high­throughput sequencing to detect the differential expression of RNA and differential genes. Si­TREM2 transfection was used to verify the important role of TREM2 in the effects of PIC. Immunohistochemical staining was used to observe the expressions of TREM2 and GSDMR of tumor in nude mice after PIC administration. PIC effectively inhibited proliferation ability of C918 and Mum­2b UM cell lines via enhancing apoptosis, as evidenced by enhanced activities of caspase 3 and caspase 9. In addition, treatment of UM cells with PIC attenuated cell migration in a dose­dependent manner. PIC increased reactive oxygen species levels and suppressed the activity of the antioxidant enzymes superoxide dismutase, glutathione­S­transferase, glutathione peroxidase and catalase. PIC inhibited inflammatory responses in C918 cells. PIC treatment upregulated IL­1ß, IL­18 and Nod­like receptor protein 3 and downregulated gasdermin D (GSDMD). RNA sequencing results revealed the activation of an unconventional pyroptosis­associated signaling pathway, namely caspase 3/GSDME signaling, following PIC treatment, which was mediated by triggering receptor expressed on myeloid cells 2 (TREM2) upregulation. As an agonist of TREM2, COG1410­mediated TREM2 upregulation inhibited proliferation of C918 cells, displaying similar effects to PIC. Furthermore, PIC inhibited tumor growth via regulating the TREM2/caspase 3/GSDME pathway in a mouse model. Collectively, the present study revealed a novel mechanism underlying the inhibitory effects of PIC on UM, providing a potential treatment approach for UM in clinic.

Asunto(s)

Caspasa 3 , Melanoma , Piroptosis , Receptores Inmunológicos , Estilbenos , Neoplasias de la Úvea , Animales , Piroptosis/efectos de los fármacos , Neoplasias de la Úvea/tratamiento farmacológico , Neoplasias de la Úvea/patología , Neoplasias de la Úvea/metabolismo , Ratones , Línea Celular Tumoral , Humanos , Estilbenos/farmacología , Melanoma/tratamiento farmacológico , Melanoma/metabolismo , Melanoma/patología , Caspasa 3/metabolismo , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/genética , Proliferación Celular/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Antineoplásicos/farmacología , Movimiento Celular/efectos de los fármacos , Ratones Desnudos , Glicoproteínas de Membrana

RESUMEN

OBJECTIVE: This study evaluates the safety/efficacy of sabatolimab plus spartalizumab in patients with melanoma or non-small cell lung cancer (NSCLC). DESIGN, SETTING AND PARTICIPANTS: This is a phase 1-1b/2, open-label, multinational, multicentre study of patients with advanced/metastatic melanoma or NSCLC with ≥1 measurable lesion. INTERVENTIONS: Patients were given sabatolimab 800 mg every 4 weeks plus spartalizumab 400 mg every 4 weeks until unacceptable toxicity, disease progression and/or treatment discontinuation. OUTCOME MEASURES: The phase 2 primary outcome measure was overall response rate and secondary objectives included evaluation of the safety, tolerability, efficacy and pharmacokinetics of sabatolimab in combination with spartalizumab. RESULTS: 33 patients (melanoma n=16, NSCLC n=17) received sabatolimab plus spartalizumab. 31 (94%) experienced ≥1 adverse event (AE); 15 (46%) experienced grade 3/4 events. The most frequent grade ≥3 AEs for NSCLC were anaemia, dyspnoea and pneumonia (each n=2, 12%); for patients with melanoma, the most frequent grade ≥3 AEs were physical health deterioration, hypokalaemia, hypophosphataemia, pathological fracture and tumour invasion (each n=1; 6%). One (3%) patient discontinued treatment due to AE. Stable disease was seen in three patients with melanoma (19%) and six patients with NSCLC (35%). Median progression-free survival was 1.8 (90% CI 1.7 to 1.9) and 1.7 (90% CI 1.1 to 3.4) months for patients with melanoma and NSCLC, respectively. Patients with stable disease had higher expression levels of CD8, LAG3, programmed death-ligand 1 and anti-T-cell immunoglobulin and mucin-domain containing-3 at baseline. The pharmacokinetics profile of sabatolimab was consistent with the phase 1 study. CONCLUSIONS: Sabatolimab plus spartalizumab was well tolerated in patients with advanced/metastatic melanoma or NSCLC who had progressed following antiprogrammed death-1/antiprogrammed death-ligand 1 treatment. Limited antitumour activity was observed. The tolerability of sabatolimab administration supports the potential to explore treatment with sabatolimab in various combination regimens and across a spectrum of tumour types. TRIAL REGISTRATION NUMBER: NCT02608268.

Asunto(s)

Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Melanoma , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Femenino , Masculino , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Persona de Mediana Edad , Anciano , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacocinética , Melanoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Adulto , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Anciano de 80 o más Años

RESUMEN

BACKGROUND: Immune checkpoint inhibitors (ICIs) have significantly improved outcomes for patients with cancer. However, these therapies are associated with adverse events including de novo immune-related adverse events or flare of pre-exiting autoimmune disorders. Up to 80% of patients with cancer and pre-existing psoriasis (PsO) or psoriatic arthritis (PsA) experience PsO/PsA flare after initiating ICIs. Targeting the interleukin (IL)-17/IL-23 axis is a mainstream of the PsO/PsA treatment. However, whether this treatment can effectively control PsO/PsA with ICI exposure while preserving anti-tumour efficacy remains unknown. CASE REPORTS: We report three patients with PsA and cancer, who received ICIs for their cancer treatment. All patients were male. Two patients had clear cell renal cell carcinoma, and one had melanoma. Two patients received anti-PD-1 antibody monotherapy, while one patient received combined anti-CTLA-4 and PD-1 antibody therapy. One patient had been receiving anti-IL-17A antibody (secukinumab), while the other two patients started anti-IL-17A antibody (ixekizumab) and anti-IL-23 antibody (guselkumab) after their PsA flared up during ICI treatment. Of note, with the anti-IL-17A or anti-IL-23 antibody treatment, their PsA remained in remission, and they well tolerated the ICI therapy. Importantly, all three patients showed persistent tumour responses to ICI therapy, including two complete remissions and one stable disease, respectively. CONCLUSIONS: These three cases suggest that targeting the IL-17/23 axis may be an effective and safe approach for patients with cancer and pre-existing PsA being considered for ICI therapy.

Asunto(s)

Artritis Psoriásica , Inhibidores de Puntos de Control Inmunológico , Interleucina-17 , Interleucina-23 , Humanos , Artritis Psoriásica/tratamiento farmacológico , Masculino , Interleucina-17/antagonistas & inhibidores , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Persona de Mediana Edad , Anciano , Interleucina-23/antagonistas & inhibidores , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/etiología , Resultado del Tratamiento , Neoplasias/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/etiología , Melanoma/tratamiento farmacológico

RESUMEN

BACKGROUND/AIM: Malignant melanoma is a tumor with a poor prognosis that can metastasize distally at an early stage. Terrein, a metabolite produced by Aspergillus terreus, suppresses the expression of angiogenin, an angiogenic factor. However, the pharmacological effects of natural terrein have not been elucidated, because only a small amount of terrein can be extracted from large fungal cultures. In this study, we investigated the antineoplastic effects of terrein on human malignant melanoma cells and its underlying mechanisms. MATERIALS AND METHODS: Human malignant melanoma cell lines were cultured in the presence of terrein and analyzed. Angiogenin production was evaluated using ELISA. Ribosome biosynthesis was evaluated using silver staining of the nucleolar organizer region. Intracellular signaling pathways were analyzed using western blotting. Malignant melanoma cells were transplanted subcutaneously into the backs of nude mice. The tumors were removed at 5 weeks and analyzed histopathologically. RESULTS: Terrein inhibited angiogenin expression, proliferation, migration, invasion, and ribosome biosynthesis in malignant melanoma cells. Terrein was shown to inhibit tumor growth and angiogenesis in animal models. CONCLUSION: This study demonstrated that terrein has anti-tumor effects against malignant melanoma. Furthermore, chemically synthesized non-natural terrein can be mass-produced and serve as a novel potential anti-tumor drug candidate.

Asunto(s)

Proliferación Celular , Melanoma , Ratones Desnudos , Ribonucleasa Pancreática , Humanos , Animales , Melanoma/tratamiento farmacológico , Melanoma/metabolismo , Melanoma/patología , Ribonucleasa Pancreática/metabolismo , Ratones , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto , Movimiento Celular/efectos de los fármacos , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ciclopentanos

RESUMEN

We report a successful formulation of Artemisone (ATM) in transferrin (Tf)-conjugated nanostructured lipid carriers (NLCs), achieving nearly a five-times increase in cell toxicity. The escalating cost of new drug discoveries led to the repurposing of approved drugs for new indications. This study incorporated Artemisone, an antimalarial drug, into a nanostructured lipid carrier (NLC) and tested for possible anticancer effects. The aim was to develop NLCs, and transferrin-conjugated NLCs (NLC-Tf) encapsulating Artemisone to enhance its delivery and anticancer activity. NLC formulations were prepared using high-pressure homogenization followed by ultrasonication and were characterized by particle size, zeta potential, and PDI. The conjugation of (Tf) to (NLC) was confirmed using IR, and the anticancer activity was tested using MTS assay. All formulations were in the nanometer size range (140-167 nm) with different zeta potential values. IR spectroscopy confirmed the successful conjugation of transferrin to NLC. Upon testing the formulations on melanoma cell lines using MTS assay, there was a significant decrease in viability and an increase in the encapsulated ATM-Tf toxicity compared to positive control ATM. The NLCs presented a promising potential carrier for delivering ATM to melanoma cells, and further conjugation with Tf significantly improved the ATM cytotoxicity.

Asunto(s)

Artemisininas , Portadores de Fármacos , Lípidos , Melanoma , Nanoestructuras , Transferrina , Transferrina/química , Transferrina/farmacología , Humanos , Melanoma/tratamiento farmacológico , Melanoma/patología , Melanoma/metabolismo , Portadores de Fármacos/química , Artemisininas/química , Artemisininas/farmacología , Línea Celular Tumoral , Lípidos/química , Nanoestructuras/química , Supervivencia Celular/efectos de los fármacos , Tamaño de la Partícula , Antineoplásicos/farmacología , Antineoplásicos/química , Sistemas de Liberación de Medicamentos , Nanopartículas/química