Search Results (63)

Cutaneous malignant melanoma is an extraordinarily aggressive and heterogeneous cancer that contains a small subpopulation of tumor stem cells (CSCs) responsible for tumor initiation, metastasis, and recurrence. Identification and characterization of CSCs in melanoma is challenging due to tumor heterogeneity and the lack of specific markers (CD271, ABCB5, ALDH, Nanog) and the ability of cells to dynamically change their phenotype. Phenotype-maintaining signaling pathways (Wnt/β-catenin, Notch, Hedgehog, HIF-1) promote self-renewal, treatment resistance, and epithelial–mesenchymal transitions. Tumor plasticity reflects the ability of differentiated cells to acquire stem-like traits and phenotypic flexibility under stress conditions. The interaction of CSCs with the tumor microenvironment accelerates disease progression: they induce the formation of cancer-associated fibroblasts (CAFs) and neo-angiogenesis, extracellular matrix remodeling, and recruitment of immunosuppressive cells, facilitating immune evasion. Emerging therapeutic strategies include immunotherapy (immune checkpoint inhibitors), epigenetic inhibitors, and nanotechnologies (targeted nanoparticles) for delivery of chemotherapeutic agents. Understanding the role of CSCs and tumor plasticity paves the way for more effective innovative therapies against melanoma. Full article

Background/Objectives: Melanoma is an aggressive skin cancer influenced by genetic and immunological factors. The PDCD1 gene encodes PD-1, a receptor involved in immune evasion and therapeutic response. This study aimed to evaluate the association of PDCD1 variants (rs2227982, rs36084323, rs7421861) and its relative gene expression with melanoma in a Mexican population. Methods: An analytical cross-sectional study was conducted with 262 samples: 131 from melanoma patients (newly diagnosed and treatment-naïve) and 131 from cancer-free controls. Genotyping was performed using real-time PCR. PDCD1 expression was assessed by qPCR, normalized with GAPDH, using the 2^−ΔΔCt method and the Pfaffl model. Statistical comparisons included allele/genotype frequencies, expression levels, and clinicopathological associations. Results: No significant association was found between the studied PDCD1 variants and melanoma susceptibility. However, PDCD1 was significantly overexpressed in melanoma samples (2.42-fold increase; p < 0.01), consistent across both quantification methods. Significant associations were also observed between histopathological subtype and Breslow thickness, and between subtype and anatomical site (p < 0.01). Conclusions: Although PDCD1 variants showed no association with melanoma risk, the gene’s overexpression highlights its potential relevance in melanoma immunobiology. These findings contribute to the molecular characterization of melanoma in the Mexican population and support future research on PDCD1 as an immunological biomarker. Full article

The tumor microenvironment (TME) in advanced solid tumors is determined by immune checkpoints (PD-1, CTLA-4, and CD95) and cytokine networks (IL-2, IL-10, and TNF-α) that drive CD8+ T cell exhaustion, metabolic reprogramming, and apoptosis resistance, enabling immune evasion. Some studies revealed PD-1/CD95 co-expression is a marker of T cell dysfunction, while CTLA-4 upregulation correlates with suppressed early T cell activation. IL-10 has emerged as a potential biomarker for chemoresistance and tumor aggressivity, consistent with its role in promoting anti-apoptotic signaling in cancer stem cells (CSCs). Engineered IL-2 variants and TNF-α modulation are highlighted as promising strategies to revitalize exhausted CD8+ T cells and disrupt CSC niches. This prospective single-center study investigated the dynamic TME alterations in 16 patients with immunotherapy-naïve stage IV non-small-cell lung cancer (NSCLC) and metastatic melanoma treated with anti-PD-1 nivolumab. The longitudinal immunophenotyping of peripheral blood lymphocytes (via flow cytometry) and serum cytokine analysis (via ELISA) were performed at the baseline, >3, and >6 months post-treatment to evaluate immune checkpoint co-expression (PD-1/CD95 and CTLA-4/CD8+) and the cytokine profiles (IL-2, IL-10, and TNF-α). Full article

Non-melanoma skin cancer (NMSC), comprising basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), represents the most common type of cancer worldwide, particularly among Caucasians. While BCC is locally invasive with minimal metastatic potential, cSCC is a highly aggressive tumor with a significant potential for metastasis, particularly in elderly populations. Tumor development and progression and the metastasis of cSCC are influenced by a complex interplay between tumor cells and the tumor microenvironment. Recent research highlights the importance of various immune cell subsets, including T cells, tumor-associated macrophages (TAMs), and dendritic cells, in influencing tumor progression, immune evasion, and treatment resistance. This review outlines key regulatory mechanisms in the immune tumor microenvironment (TME) of cSCC and explores the role of cytokines, immune checkpoints, and stromal interactions. We further discuss the relevance of three-dimensional (3D) in vitro models such as spheroids, organoids, and tumor-on-chip systems as tools to mimic immune–tumor interactions with higher physiological relevance, such as macrophage activation and polarization against cSCC cells. Globally, 3D models offer new opportunities for immunotherapy screening and mechanistic studies. Understanding the immune landscape in cSCC through advanced modeling techniques holds strong clinical potential for improving diagnostic and therapeutic strategies. Full article

Background/Objectives: This review discusses the resistance mechanisms in the tumor microenvironment (TME) of malignant melanoma that disrupt the efficacy of immune checkpoint inhibitors (ICIs). In this review, we focus on the roles of immune cells, including tumor-infiltrating lymphocytes (TILs), macrophages, dendritic cells, and other signaling pathways. We explore the interplay between innate and adaptive immunity in the TME and tumor intrinsic resistance mechanisms, such as β-catenin, which has future implications for the usage of ICIs in patients with therapy-resistant tumors. Methods: A total of 1052 studies were extracted from the PubMed database searching for keywords and phrases that included [melanoma AND immune checkpoint inhibitor resistance]. After a title/abstract and full-text review, 101 studies were identified that fit the inclusion/exclusion criteria. Results: Cancer-associated fibroblasts (CAFs), M2 macrophages, and myeloid-derived suppressor cells (MDSCs) are significant in remodeling the TME to promote melanoma growth. Melanoma resistance to ICIs is complex and involves TME alterations, tumor intrinsic factors, and immune evasion. Key components of resistance include reduced CD8+ T cell infiltration, decreased host immune response, and immunosuppressive cytokines. Conclusions: Predictive biomarkers and specific models are the future of individualized melanoma management and show great promise in their approach to targeted therapy production. Tumor profiling can be utilized to help predict the efficacy of ICIs, and specific biomarkers predicting therapy responses are instrumental in moving towards personalized and more efficacious medicine. As more melanoma resistance emerges, alternative and combinatorial therapy based on knowledge of existing resistance mechanisms will be needed. Full article

Cutaneous melanoma is an aggressive cancer with an increasing incidence worldwide, highlighting the need for research into its pathogenesis. The tumor microenvironment (TME) plays a critical role in melanoma progression and consists of cellular components and an extracellular matrix (ECM) rich in cytokines and signaling molecules. The most abundant stromal cells within the TME are cancer-associated fibroblasts (CAFs), which remodel the ECM and modulate immune responses. Among immune cells, tumor-associated macrophages (TAMs) predominate, and their polarization toward the M2 phenotype supports tumor progression. Tumor-infiltrating lymphocytes (TILs) have diverse functions, including cytotoxic T-cells, helper T-cells that modulate immune response, B-cells forming tertiary lymphoid structures (TLS), and regulatory T-cells with immunosuppressive properties. Dendritic cells (DCs) also play a complex role in the TME. A notable subpopulation are mature regulatory dendritic cells (mregDCs), which contribute to immune evasion. All of these TME components may drive tumorigenesis. Advancements in melanoma treatment—including immunotherapy and targeted therapies—have significantly improved outcomes in advanced-stage disease. In parallel, emerging approaches targeting the tumor microenvironment and gut microbiome, as well as personalized strategies such as neoantigen vaccines and cell-based therapies, are under active investigation and may further enhance therapeutic efficacy in the near future. Full article

NRAS-mutant melanoma represents a clinically challenging subset of melanoma with limited effective therapies and intrinsic resistance to targeted MEK inhibition. Recent findings highlight protein S-nitrosylation, a redox-dependent post-translational modification as a critical modulator of MEK-ERK signaling and immune evasion in this context. In this commentary, we discuss how S-nitrosylation of MAPK components, including MEK and ERK, sustains oncogenic signaling and attenuates immunogenic cell death. Targeting this modification with nitric oxide synthase (NOS) inhibitors such as L-NAME, L-NMMA and 1400w restore sensitivity of MEK inhibitor, promotes dendritic cell activation, and enhances CD8+ T cell infiltration in preclinical models such as immunogenic mouse models and individual patient derived, primary melanoma cells. We also explore the emerging role of S-nitrosylation in regulating macrophage-mediated immune surveillance and propose translational strategies for combining redox modulation with targeted and immune therapies. These insights offer a compelling framework for overcoming therapeutic resistance and reprogramming the tumor immune microenvironment to activate the cytotoxic T-cells and enhance the responses to immunotherapy in NRAS-driven cancers. Full article

Background/Objectives: Natural killer (NK) cells play a crucial role in immune surveillance against melanoma, yet they frequently exhibit dysfunction in the tumor microenvironment. This study aims to establish an NK cell activation-related prognostic signature and identify potential druggable targets to overcome NK cell dysfunction. Methods: A prognostic signature was developed using the TCGA-SKCM cohort and validated across independent datasets. NK cell activation and cytotoxicity were evaluated in melanoma-NK-92MI co-culture systems via flow cytometry. Mechanistic studies employed Western blotting, co-immunoprecipitation, ELISA, and qRT-PCR. Single-cell RNA-seq data were used to analyze cell–cell communication. Results: A four-gene NK cell activation signature was identified and validated for prognostic significance across five independent melanoma datasets. Among the identified genes, cyclin B1 (CCNB1) emerged as a novel therapeutic target for overcoming NK cell resistance. In vivo, pharmacological inhibition of the CCNB1/Cyclin-dependent kinase 1 (CDK1) complex with RO-3306 significantly suppressed melanoma growth by enhancing NK cell infiltration and IFN-γ production. In vitro, CCNB1 knockdown in melanoma cells augmented NK-92MI activation, as evidenced by increased expression of CD69, CD107a, IFN-γ, and NKG2D, thereby improving NK cell-mediated cytotoxicity. Mechanistically, in melanoma cells, the CCNB1/CDK1 complex phosphorylates STAT3, activating the IL-6/STAT3 positive feedback loop, which upregulates PD-L1 and enables resistance to NK cell-mediated cytotoxicity. Beyond its role in immune evasion, CCNB1 also promoted melanoma invasiveness by inducing epithelial–mesenchymal transition (EMT) through the TGF-β-SMAD2/3 signaling. Conclusions: This study establishes CCNB1/CDK1 as a novel immunotherapeutic target and uncovers a new role for CDK1 inhibitors in enhancing NK cell function and suppressing melanoma progression. Full article

Background/Objectives: Melanoma remains a difficult malignancy to treat because it employs tolerance mechanisms like negative immune checkpoint (IC) molecules to avoid antitumor immune responses. Thus, immune checkpoint inhibitors (ICIs) are increasingly used to treat melanoma. However, many patients do not respond, indicating resistance mechanisms like intrinsic tumor characteristics and an immunosuppressive tumor microenvironment (TME). An inflamed TME was associated with improved ICI efficacy by upregulating the T-cell inflamed TME gene signatures, an array of genes associated with dendritic cells (DCs) and cytotoxic CD8⁺ T-cell-mediated anti-tumor responses. As histone deacetylases (HDACs) have been shown to play crucial roles in regulating gene expression and aberrant HDAC expression has been reported in melanoma and also implicated in the regulation of IC, programmed cell death protein 1 (PD-1), and its ligand (PD-L1) and various immune evasion genes, we investigated the relationship between T-cell inflamed TME gene signatures and the HDAC family, particularly HDAC4. Methods: We used the skin cutaneous melanoma (SKCM) database, ICI-pretreated melanoma dataset, and other platforms including cBioPortal, TIMER 2.0, TISIDB, and UALCAN for the analysis. Results: We identified that high HDAC4 expression negatively modulated the TME by decreasing the abundance of DCs and cytotoxic CD8⁺ T-cells. The group of melanoma patients with elevated HDAC4 expression exhibited not only poor prognosis but also diminished transcription of T-cell inflamed TME gene signatures and increased DNA methylation of T-cell inflamed TME gene signatures. Importantly, elevated HDAC4 expression was associated with decreased CD8⁺ T-cells and a decreased ESTIMATE immune score in ICI-pretreated melanoma patients. Conclusions: Our findings suggest that HDAC4 may transform the TME into a non-inflamed phenotype, thereby reducing ICI efficacy in melanoma. Overall, this research shows that a combination of HDAC4 inhibitors and ICIs could result in better melanoma prognosis. Full article

Sarcomas are a heterogeneous group of malignancies with limited therapeutic options, particularly in the metastatic setting. Adoptive cellular therapies (ACTs), including tumor-infiltrating lymphocyte (TIL) therapy, chimeric antigen receptor (CAR) T-cell therapy, and T-cell receptor (TCR) gene-modified T-cell therapy, offer promising novel approaches for these refractory tumors. TIL-based therapy has demonstrated early efficacy in melanoma and myeloma, with ongoing trials exploring its role in sarcoma. CAR T-cell strategies targeting HER2, GD2, and B7-H3 antigens are in development, though challenges such as tumor microenvironment-mediated resistance and antigen escape remain significant. Engineered TCRs, particularly those targeting MAGE-A4 and NY-ESO-1, have shown promising clinical results in synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCLS), leading to the recent FDA approval of afamitresgene autoleucel (afami-cel) and letetresgene autoleucel (lete-cel). Despite encouraging preliminary data, ACT implementation faces barriers including limited antigen specificity, off-tumor toxicity, immune evasion, and manufacturing scalability. Future research will focus on optimizing lymphodepleting regimens, mitigating toxicity, enhancing in vivo persistence, and combining ACT with other therapeutic agents. As clinical trials expand, ACT holds the potential to revolutionize sarcoma treatment by offering durable, targeted therapies for previously refractory disease. Full article

Background/Objectives: Cutaneous melanoma (CM) is a highly aggressive malignancy with poor prognosis, necessitating novel biomarkers and therapeutic targets. Centromere protein F (CENPF), a mitotic regulator, has been implicated in tumor progression, but its role in melanoma remains unclear. This study aimed to investigate the clinical significance, biological function, and regulatory mechanisms of CENPF in melanoma. Methods: Public melanoma datasets (GSE46517, GSE3189, and GSE7553) were re-analyzed to identify differentially expressed genes (DEGs). CENPF expression was validated in clinical samples (n = 128), melanoma cell lines, and xenograft models. Functional assays (EdU, CCK-8, colony formation, wound healing, transwell, and flow cytometry) and bioinformatics analyses (GO, KEGG, GSEA, and SCENIC) were performed to assess proliferation, apoptosis, metastasis, and regulatory pathways. In vivo tumorigenesis and metastasis were evaluated in BALB/c nude mice. Results: CENPF was significantly upregulated in melanoma tissues and cell lines compared to controls (p < 0.05). High CENPF expression correlated with advanced Clark level (p = 0.006), ulceration (p = 0.04), and poor overall survival (p = 0.005). Knockdown of CENPF suppressed melanoma cell proliferation, migration, and invasion in vitro, while inducing G2/M phase arrest and apoptosis. In vivo, CENPF silencing reduced tumor growth and lung metastasis. Mechanistically, CENPF was transcriptionally activated by E2F3, and the E2F3-CENPF axis promoted cell cycle progression via G2/M checkpoint activation and P53 pathway suppression. Conclusions: CENPF serves as a prognostic biomarker and therapeutic target in melanoma. Its upregulation drives tumor progression through cell cycle dysregulation and immune evasion, while targeting the E2F3-CENPF axis may offer a novel strategy for melanoma treatment. These findings provide critical insights into melanoma pathogenesis and potential clinical applications. Full article

UL-16 binding protein 2 (ULBP2), a human NKG2D ligand, has been identified as a poor prognostic factor in several cancers based on recent comprehensive analyses of immune-related genes using the Cancer Genome Atlas datasets. Despite its clinical significance, the functional role of ULBP2 in vivo remains largely unknown. In this study, we investigated the role of ULBP2 in modulating anti-tumor immunity using murine melanoma cell lines engineered to stably express surface-expressed or soluble ULBP2. Subcutaneous transplantation of ULBP2-expressing melanoma cells into syngeneic mice resulted in accelerated tumor growth, mediated by surface-expressed ULBP2, through the suppression of NKG2D-dependent immune responses. In vitro experiments revealed that sustained exposure to tumor-expressed ULBP2 reduced NKG2D expression and cytotoxic activity of splenocytes. In contrast, soluble ULBP2 did not significantly affect tumor growth or immune responses. These findings suggest that surface-expressed ULBP2 plays a pivotal role in tumor immune evasion and highlight its potential as a therapeutic target to enhance anti-tumor immunity. Full article

Immune checkpoint inhibition is a major component in today’s cancer immunotherapy. In recent years, the FDA has approved a number of immune checkpoint inhibitors (ICIs) for the treatment of melanoma, non-small-cell lung, breast and gastrointestinal cancers. These inhibitors, which target cytotoxic T-lymphocyte antigen-4, programmed cell death (PD-1), and programmed cell death ligand (PD-L1) checkpoints have assumed a leading role in immunotherapy. The same inhibitors exert significant antitumor effects by overcoming tumor cell immune evasion and reversing T-cell exhaustion. The initial impact of this therapy in cancer treatment was justly described as revolutionary, however, clinical as well as research data which followed demonstrated that these innovative drugs are costly, are associated with potentially severe adverse effects, and only benefit a small subset of patients. These limitations encouraged enhanced research and clinical efforts to identify predictive biomarkers to stratify patients who are most likely to benefit from this form of therapy. The discovery and characterization of this class of biomarkers is pivotal in guiding individualized treatment against various forms of cancer. Currently, there are three FDA-approved predictive biomarkers, however, none of which on its own can deliver a reliable and precise response to immune therapy. Present literature identifies the absence of precise predictive biomarkers and poor understanding of the mechanisms behind tumor resistance as the main obstacles facing ICIs immunotherapy. In the present text, we discuss the dual role of PD-L1 as a biomarker for response to immunotherapy and as an immune checkpoint. The contribution of mass spectrometry-based analysis, particularly the impact of protein post-translational modifications on the performance of this protein is underlined. Full article

Background: Programmed cell death protein 1 (PD-1), encoded by the PDCD1 gene, is critical in immune checkpoint regulation and cancer immune evasion. Variants in PDCD1 may alter its function, impacting cancer susceptibility and disease progression. Objectives: This study evaluates the structural, functional, and regulatory impacts of non-synonymous single-nucleotide polymorphisms (nsSNPs) in the PDCD1 gene, focusing on their pathogenic and oncogenic roles. Methods: Computational tools, including PredictSNP1.0, I-Mutant2.0, MUpro, HOPE, MutPred2, Cscape, Cscape-Somatic, GEPIA2, cBioPortal, and STRING, were used to analyze 695 nsSNPs in the PD1 protein. The analysis covered structural impacts, stability changes, regulatory effects, and oncogenic potential, focusing on conserved domains and protein–ligand interactions. Results: The analysis identified 84 deleterious variants, with 45 mapped to conserved regions like the Ig V-set domain essential for ligand-binding interactions. Stability analyses identified 78 destabilizing variants with significant protein instability (ΔΔG values). Ten nsSNPs were identified as potential cancer drivers. Expression profiling showed differential PDCD1 expression in tumor versus normal tissues, correlating with improved survival in skin melanoma but limited value in ovarian cancer. Regulatory SNPs disrupted miRNA-binding sites and transcriptional regulation, affecting PDCD1 expression. STRING analysis revealed key PD-1 protein partners within immune pathways, including PD-L1 and PD-L2. Conclusions: This study highlights the significance of PDCD1 nsSNPs as potential biomarkers for cancer susceptibility, advancing the understanding of PD-1 regulation. Experimental validation and multi-omics integration are crucial to refine these findings and enhance theraputic strategies. Full article

Background and Objectives: This study explores the immunological landscapes of non-melanoma skin neoplasms (NMSNs), specifically keratoacanthoma (KA), squamous cell carcinoma (SCC), and common warts (VV). Although benign, KA shares histological similarities with low-grade SCC. The tumor microenvironment (TME) plays a key role in tumor progression, affecting angiogenesis, inflammation, and immune evasion. Viral infections, particularly human papillomavirus (HPV), are linked to NMSN development, with various HPV types identified in KA. VV, caused by HPV, serves as a comparative model due to its similar etiopathogenesis. Materials and Methods: This research examines the expression of CTLA4, a critical regulator of T-cell homeostasis, and IFN-γ, a cytokine with immunomodulatory and antiviral effects, in the TME of 41 KA, 37 SCC, and 55 VV samples using multichannel immunofluorescence. Results: The analysis revealed distinct patterns of CTLA4 and IFN-γ expression. SCC exhibited a higher prevalence of CTLA4+IFN-γ+ double-positive lymphocytes, suggesting a more immunosuppressive TME. In contrast, VV showed the highest expression of CTLA4+ cells, while both KA and VV had lower expressions of IFN-γ+ lymphocytes compared to SCC. The increased presence of CTLA4+IFN-γ+ double-positive lymphocytes in SCC suggests that the co-expression of these markers may exert a stronger effect on TME modulation than CTLA4 alone. Conclusions: These findings underscore the potential of immune profiling as a diagnostic tool to differentiate between benign and malignant lesions, such as KA and SCC. Furthermore, the presence of CTLA4+IFN-γ+ lymphocytes, particularly in SCC, may serve as a biomarker for tumor progression and a potential target for future immunotherapy strategies aimed at modulating the immune response in NMSN. Full article