Luciana Cavalheiro Marti

Cutaneous melanoma remains a leading cause of skin cancer-related mortality despite significant therapeutic advances, with treatment resistance and immune evasion representing major clinical challenges. Epigenetic dysregulation, particularly through the histone methyltransferases G9a (EHMT2) and Enhancer of Zeste Homolog 2 (EZH2), plays a pivotal role in melanoma progression, therapeutic resistance, and immune escape. G9a catalyzes the deposition of H3K9me2, whereas EZH2, the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2), mediates H3K27me3 deposition, thereby establishing repressive chromatin states that silence tumor suppressor genes and immune-related pathways. These enzymes are frequently overexpressed in melanoma and cooperate to maintain dedifferentiated and invasive tumor phenotypes characterized by enhanced plasticity and reduced immunogenicity. Acral melanoma, a distinct subtype with a low ultraviolet (UV) mutational burden, appears to be particularly dependent on epigenetic reprogramming and exhibits an immunologically “cold” tumor microenvironment that is associated with poor responses to current therapies. Preclinical studies demonstrate that pharmacological inhibition of G9a with compounds such as UNC0642 and EZH2 with agents including tazemetostat can restore the expression of silenced genes, enhance antigen presentation, and improve tumor immunogenicity. Importantly, the functional crosstalk between G9a and EZH2 creates redundant repressive mechanisms that may limit the efficacy of single-agent therapies supporting the development of combination strategies targeting both pathways. Dual inhibition has shown promise in pre-clinical models by converting immune-excluded “cold” tumors into immune-responsive “hot” tumors that are more susceptible to checkpoint blockade and adoptive cell therapies. While EZH2 inhibitors have progressed to clinical trials in various solid tumors, melanoma-specific studies remain limited despite strong biological rationale. This review synthesizes the current understanding of G9a and EZH2 biology in melanoma, evaluates therapeutic targeting strategies, and highlights the potential for epigenetic reprogramming to overcome treatment resistance and enhance immunotherapy responses in this aggressive malignancy.

Introduction: Tissue-derived chemokines can direct immune cell migration by engaging specific receptors, thereby controlling the localization and trafficking of immune cells within tissues. However, how chemokines modulate cytokines-driven transcriptional programs in T cells remain unclear. This study investigated how CXCL8 and CCL20 influence human T cell responses to IL-15 and IL-32α. Methods: Peripheral blood T cells from health donors were evaluated for the expression and functional activity of the chemokine receptors CCR6, CXCR1, and CXCR2. Chemokine induced migration was assessed using in vitro migration assays. T cells were stimulated with CCL20 or CXCL8 alone or in combination with IL-15 or IL-32α, and transcriptional responses were characterized by transcriptomic profiling. Selected transcriptional findings were further evaluated through functional and protein-level assays. Results: Peripheral blood T cells expressed CCR6, CXCR1, and CXCR2, which were downregulated during vitro culture, but remained functionally responsive in migration assays, highlighting the influence of the microenvironmental on receptor expression. Transcriptomic profiling showed that CCL20 and CXCL8 independently reprogrammed GPCR-associated networks involved in migration, cytoskeletal dynamics, adhesion, and chemokine scavenging. IL-15 induced robust JAK/STAT-dependent inflammatory and survival programs together with CISH upregulation, indicating coordinated activation and negative-feedback regulation. In contrast, IL-32α modulated PI3K/AKT, adhesion, and NOTCH1-related pathways and was associated with increased T cell proliferation. Combined stimulation revealed context-dependent integration of these signaling programs. IL-15 plus CCL20 enhanced inflammatory and migratory signatures, whereas CXCL8 plus IL-15 produced a transcriptional profile largely dominated by IL-15. IL-32α plus CXCL8 induced cooperative programs involving vesicular remodeling, mTOR-associated metabolism, cytoskeletal organization, and cell-cycle regulation. Discussion: These findings demonstrated that chemokine and cytokine signals are integrated in a context-dependent manner to regulate T cells migration, activation, survival and proliferation. Rather than acting solely as chemoattractant, CCL20 and CXCL8 can reshape cytokine-driven transcriptional profile programs, revealing additional regulatory layer that may contribute to T cell functional plasticity within inflammatory and tumor microenvironment.

CCR10, the latest classified receptor in the CC chemokine family, plays a critical role in tissue-specific immune responses, particularly in skin and mucosal immunity. By interacting with its ligands, CCL27 and CCL28, it regulates immune cell trafficking, contributing to homeostasis, wound healing, and mucosal defense. However, CCR10 has also been implicated in inflammatory disorders, autoimmune diseases, and cancer progression, where it may facilitate immune evasion and metastasis. Despite its dual roles, CCR10 represents a promising therapeutic target, potential applications in modulating immune responses for inflammatory diseases and oncology. A deeper understanding of its mechanisms and interactions could provide valuable insights into immune system regulation, disease progression and clinical relevance. This review explores CCR10’s molecular structure, biological functions, and potential for therapeutic intervention.

The purpose of this study was to evaluate normal values of healthy human bone marrow (n = 56) and identify gender- and age-related variations using cell lineage markers and maturational curves. Using 10-color quantitative flow cytometry, various cell types were identified, including B cells, T cells, NK cells, granulocytes, monocytes, erythroblasts, plasma cells, basophils, mast cells, and dendritic cells. Results revealed significant age-related declines in the absolute counts of nucleated cells (p = 0.001), including CD34+ immature B cells (p = 0.006) and CD34- immature B cells (p = 0.004). Declines were also observed for T cells (p = 0.002), cytotoxic T cells (p < 0.001), double-negative T cells (p = 0.0001), NK cells (p = 0.007), CD16- NK cells (p < 0.001), metamyelocytes (p = 0.002), neutrophils (p = 0.001), basophils (p = 0.009), promonocytes (p = 0.001), mature monocytes (p = 0.007), and plasmacytoid dendritic cells (p = 0.001). Gender differences showed males had more intermediate monocytes (p = 0.009) compared to females. In summary, this study provides normal values for hematopoietic cells, highlighting age- and gender-related disparities critical for understanding hematopoietic dynamics.

Introduction: Innate lymphoid cells (ILCs) are a recently characterized subset of lymphocytes with critical effector and regulatory functions. Based on distinct phenotypic markers and cytokine secretion profiles, ILCs are classified into three subtypes: ILC1, ILC2, and ILC3. The bone marrow (BM) microenvironment in myelodysplastic neoplasms (MDS) is characterized by heightened cytokine levels and dysregulated inflammatory responses, potentially affecting immune cell composition. In this study, we aimed to assess the frequency and absolute number of ILCs in the BM and peripheral blood (PB) of healthy individuals (HI) and compare them to those in MDS-BM.Methods: ILC subsets were identified and quantified using multiparameter flow cytometry and histological analysis of BM and PB samples.Results: ILC1 populations were consistently detected in all PB and BM samples. In contrast, ILC2 and ILC3 subsets were present in both BM and PB of healthy individuals but were largely absent in MDS-BM samples. Additionally, our findings suggest the existence of a potential maturation trajectory for BM-resident ILCs.Discussion: These data indicate a disruption in the ILC maturation continuum within the MDS-affected BM compared to healthy BM, potentially contributing to the immunopathogenesis of MDS.

Invasive cutaneous melanoma is responsible for about 5% of skin tumors yet is liable for nearly 70% of skin cancer-related deaths. Despite notable advancements over the past decade, including immunotherapies and targeted treatments, more than half of invasive melanoma patients ultimately succumb to the disease due to therapeutic resistance. To overcome this obstacle, strategies such as combining immunotherapies with targeted drugs or adding epigenetic therapies have been investigated. Tumor-infiltrating lymphocytes (TILs) therapy has emerged as a promising option for patients whose disease continues to progress despite standard treatments. This article aims to introduce TIL therapy and review recent outcomes in melanoma prognosis in its application for melanoma management.

Hematopoiesis is characterized by the differentiation and maturation of multipotent stem cells into hematopoietic cells. Common lymphoid progenitor cells differentiate into B and T lymphocytes; natural killer cells can also originate from common lymphoid progenitors. In recent years, a cellular subtype of lymphocytes, called innate lymphocytes, has been described. Innate lymphoid cells (ILCs) play an important effector and regulatory role in innate immunity, and similar to natural killer cells, depend on the γc and Id2 chains for their development.

Cytomegalovirus (CMV) poses a significant threat to post-hematopoietic cell transplantation (HCT). Control strategies include letermovir prophylaxis or ganciclovir pre-emptive therapy (PET). Without prophylaxis, 65–90% of seropositive recipients develop a clinically significant CMV infection. Due to PET drawbacks, letermovir prophylaxis is preferable, as it reduces CMV-related events and improves overall survival. However, refractory or resistant CMV-CS remains a challenge, with maribavir showing limited efficacy. This systematic review followed the Cochrane Manual and PRISMA guidelines and was registered in PROSPERO. Searches were conducted in PubMed, Scopus, Embase, and Web of Science. Out of 1895 identified records, 614 duplicates were removed, and subsequent screening excluded 1153 studies. Eleven included studies (2012–2024) involved 255 HCT recipients receiving adoptive immunotherapy (AI), primarily CMV-specific T-cell therapy. GvHD occurred in 1.82% of cases. Adverse events occurred in 4.4% of cases, while mild CRS was observed in 1.3% of patients. Efficacy, evaluated in 299 patients across eleven studies, showed an average response rate of 78.2%. CMV-CS recurrence was observed in 24.4% of 213 patients, and death due to CMV was reported in 9.7% of 307 patients across nine studies. Adoptive hCMV-specific T-cell immunotherapy appears to be a safe, effective alternative for refractory CMV-CS in HCT.

RNA interference (RNAi) is a gene-silencing process elicited by double-stranded RNAs. This methodology can be used for analyzing loss-of-function phenotypes and has highly contributed for cells molecular biology research field. This study was conducted in order to optimize siRNA transfection and virus-mediated short-hairpin RNA (vshRNA) for silencing CXCL12 mRNA in human bone marrow mesenchymal stem cells (BM-hMSC) intending further studies on its role in hematopoietic stem cells (HSC) in the bone marrow niche. CXCL12 mRNA levels transient reduction was observed after siRNA transfection for silencing CXCL12 mRNA. However, there were no significant differences in intracellular CXCL12 protein levels or in cultures supernatant. On the other hand, the transduction of CXCL12-targeting vshRNA resulted in downregulation of the CXCL12 mRNA and protein levels in both intracellular compartment and culture supernatant of BM-hMSCs. Our results demonstrated very high level of transduction efficiency, without repeated rounds of infection, neither cell sorting nor antibiotic selection and with no major changes in cell viability or morphology. Thus, the current study presents an effective method for functional virus transduced BM-hMSC. In addition, this study discusses the requirement for testing candidate sequences and shRNA screening before confirming their effectiveness. Additionally, this study demonstrated that a gene reporter as green fluorescent protein (GFP) signal is not necessary closely correlated with knockdown efficiency.