Search Results (1,392)

Moringa oleifera, widely recognized as the horseradish tree or drumstick tree, is classified within the Moringaceae family, which comprises 13 species predominantly distributed across tropical and subtropical regions. The plant possesses a variety of therapeutic, nutritional, and beneficial health properties, including its potential to enhance the immune system. The present work provides extensive bibliographic research addressing the chemical composition of Moringa oleifera and its immunomodulatory properties with a focus on the cellular and molecular mechanisms involved in the regulation of immune function, which is crucial in unchecked cell proliferation and metastasis. The chemical composition of Moringa oleifera, including kaempferol, chlorogenic acid, quercetin, and niazimicin, varies between different biological parts of the plant (seeds, leaves, roots, and stems). The presence of these various chemical compounds contributes to the plant’s effect on the immune response via different pathways. Several studies indicate that Moringa oleifera mitigates inflammation by suppressing key pro-inflammatory mediators, such as TNF-α, IL-1β, inducible nitric oxide synthase (iNOS), prostaglandin E2 (PGE-2), and cyclooxygenase-2 (COX-2), while simultaneously enhancing anti-inflammatory mediators through activation of PPAR-γ. Furthermore, the immunomodulatory properties and possible application in health promotion and disease prevention, especially in cancer therapy, are discussed. Studies indicate that Moringa oleifera can modulate the tumor microenvironment (TME) by reducing Treg polarization, enhancing NK cell cytotoxicity, and prompting the proliferation and clonal expansion of CD8⁺ and CD4⁺ T lymphocytes. Together, Moringa oleifera could be considered for the treatment of conditions related to immune dysregulation, such as cancer. Full article

Cigarette smoking is the leading preventable cause of chronic diseases (e.g., COPD, cardiovascular disease, cancer), largely driven by persistent immune-inflammatory mechanisms. This review synthesizes the molecular and cellular cascades linking cigarette smoke (CS) exposure to chronic pathology. CS constituents, particularly ROS/RNS, induce rapid oxidative stress that overwhelms antioxidant defenses and generates damage-associated molecular patterns (DAMPs). These DAMPs activate pattern recognition receptors (PRRs) and the NLRP3 inflammasome, initiating NF-κB signaling and the release of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). CS exposure causes profound innate immune dysregulation, including airway epithelial barrier disruption, hyperactivated neutrophils, and dysfunctional alveolar macrophages (AMs) that release destructive proteases (e.g., MMP-12) and acquire foam-cell–like characteristics. Furthermore, CS drives adaptive immunity toward a Th1/Th17-dominant phenotype while suppressing regulatory T-cell (Treg) function, thereby promoting autoimmunity and chronic tissue injury. Critically, CS induces epigenetic reprogramming (e.g., DNA methylation, miRNA dysregulation), locking immune cells into a persistent pro-inflammatory state. This convergence of oxidative stress, innate and adaptive immune dysregulation, and epigenetic alterations underlies the systemic low-grade inflammation that fuels smoking-related chronic diseases, highlighting key targets for novel therapeutic interventions. Full article

Glioblastoma (GBM) remains one of the most lethal brain tumors, characterized by extensive immune evasion and a macrophage-dominated tumor microenvironment (TME). However, the molecular determinants governing tumor-associated macrophage (TAM) states and their immunoregulatory functions remain poorly understood. We integrated bulk- and single-cell transcriptomic datasets (TCGA, CGGA, Ivy GAP, and Brain Immune Atlas) to systematically characterize the expression, prognostic relevance, and immune contexture of the myeloid biomarker membrane-spanning 4-domain A6A, MS4A6A, in GBM. Differential expression, survival, and pathway enrichment analyses were performed. Single-cell mapping and CellChat modeling delineated MS4A6A-associated TAM subpopulations, intercellular communication networks, and ligand–receptor signaling dynamics. Spatial transcriptomic validation and pharmacogenomic modeling were conducted to assess anatomic enrichment and therapeutic vulnerabilities. High MS4A6A expression predicted unfavorable survival and correlated with increased stromal and immune infiltration. Single-cell analyses localized MS4A6A predominantly to TAMs, especially Regulatory- and Ribo-TAM states enriched for antigen presentation, T-cell regulation, and ribosomal biogenesis pathways. CellChat analysis revealed that MS4A6A-high TAMs exhibited markedly enhanced communication with CD4⁺ T cells and Tregs through upregulated PGE₂–PTGER2/PTGER4, PECAM1–CD38, and THBS1–CD36 signaling axes, implicating MS4A6A in prostaglandin-driven immune suppression. Spatial profiling confirmed preferential localization of MS4A6A within perivascular and angiogenic niches. Pharmacogenomic prediction indicated that MS4A6A-high tumors were more sensitive to ERK, mTOR, and CDK4/6 inhibition. MS4A6A defines a macrophage-centered, immunosuppressive ecosystem in GBM, mediated by the activation of the PGE₂ signaling axis. These findings position MS4A6A both as a prognostic biomarker and as a potential therapeutic node linking myeloid reprogramming to actionable pathway vulnerabilities in glioblastoma. Full article

Primary immune regulatory disorders (PIRDs) are a group of conditions characterised by a loss of immune tolerance. Two such disorders, CHAI and LATAIE, share common molecular mechanisms, leading to significant clinical overlap. Here, we report demographic, clinical, immunological, and molecular findings in 29 patients referred from different parts of India with a diagnosis of CHAI or LATAIE. LATAIE patients demonstrated a higher prevalence of consanguinity, while CHAI patients more often had a positive family history. Both disorders presented with overlapping clinical features, predominately autoimmune cytopenias, benign lymphoproliferation, and inflammatory bowel disease (IBD). However, the incidence of recurrent infections, otitis media, bronchiectasis, and hypogammaglobulinemia was higher among LATAIE patients as compared to CHAI. Flow cytometry analysis revealed significant differences in T cell subsets, particularly in percentages of CD4+ naïve cells and T regulatory cells (Treg), between the two disorders. B cell abnormalities were also observed. Molecular diagnosis was achieved using targeted or clinical exome sequencing, and specific protein expression was employed to validate the novel variants. Full article

T cells and B cells are central components of the adaptive immune system, orchestrating immune responses through a complex network of interactions. This review explores the dynamic interplay between T and B cells, focusing on their development, activation, and functional coordination in immune defense. T cells provide essential help to B cells through cytokine signaling and direct cell–cell interactions, facilitating antibody production and affinity maturation in germinal centers. Conversely, B cells contribute to antigen presentation and cytokine modulation, influencing T cell differentiation and function. The regulation of these interactions is critical for maintaining immune homeostasis, preventing autoimmunity, and enhancing vaccine efficacy. Dysregulation of T-B cell crosstalk is implicated in various immune disorders, including autoimmune diseases and immunodeficiencies. Recent advances in immunotherapy have targeted these pathways to modulate immune responses in conditions such as cancer, infections, and inflammatory diseases. This review synthesizes current knowledge on T and B cell physiology, highlighting emerging research on their cooperative mechanisms. Full article

HER2 (human epidermal growth factor receptor 2) is a receptor tyrosine kinase which is overexpressed in ~20% of patients with oesophagogastric adenocarcinoma (EGA). HER2 represents a targetable transmembrane glycoprotein receptor of the epidermal growth factor receptor (EGFR) family, which plays a crucial role in cell proliferation, survival, and differentiation. HER2 significantly influences the tumour microenvironment (TME) through various mechanisms, creating a niche that supports tumour progression, immune evasion, and therapeutic resistance. In HER2-positive EGA, aberrant signalling pathways, such as PI3K/AKT and MAPK/ERK, enhance tumour cell survival and proliferation, whilst upregulation of angiogenic factors like VEGF fosters vascularization, meeting a tumour’s metabolic demands and facilitating its proliferation. HER2 also modulates the tumour immune microenvironment (TIME) by downregulating MHC molecules and recruiting immunosuppressive cells, including regulatory T-cells (T-reg) and tumour-associated macrophages (TAMs), which release cytokines that further inhibit anti-tumour immune responses. Together, these factors foster a pro-inflammatory, immunosuppressive microenvironment that underpins resistance to HER2-targeted therapies. As more HER2-directed treatments become available, such as trastuzumab–deruxtecan (T-DXd), gaining a deeper understanding of the multifaceted influence of HER2 on the TME in EGA will be crucial for the development of improved targeted treatments that can overcome these challenges and lead to advancements in targeted treatment for HER2-overexpressing EGA. This review provides a comprehensive overview of the impact of HER2 on the TME in EGA and highlights the challenge it represents as well as the opportunity for novel therapeutic development and the implications for patients in terms of clinicopathological outcomes. Full article

Mitomycin-C (MMC) is the leading chemotherapeutic agent for the treatment of non-muscle invasive bladder cancer (NMIBC), but recurrence rates remain high due to poorly understood interactions between the tumor, immune system, and drugs. We present a five-equation mathematical model that explicitly tracks MMC, tumor cells, dendritic cells (DCs), effector T cells, and regulatory T cells (Tregs). The model incorporates clinically realistic treatment regimens (6-week induction followed by maintenance therapy), including DC activation by tumor debris, dual DC activation of effector and Treg cells, and reversal of MMC-induced immunosuppression. The resulting nonlinear system exhibits hidden multiscale dynamics. We apply the singular perturbed vector field (SPVF) method to identify fast–slow hierarchies, decompose the system, and conduct stability analysis. Our results reveal stable equilibria corresponding to either tumor eradication or persistence, with a critical dependence on the initial tumor size and growth rate. Modeling shows that increased DC production paradoxically contributes to treatment failure by enhancing Treg activity—a non-monotonic immune response that challenges conventional wisdom. These results shed light on the mechanisms of NMIBC evolution and highlight the importance of balanced immunomodulation in the development of therapeutic strategies. Full article

The tumor microenvironment (TME) orchestrates tumor growth, immune evasion, and therapeutic response in head and neck squamous cell carcinoma (HNSCC). Current immune checkpoint inhibitors (ICIs) target the programmed death receptor-1/programmed death-ligand 1 (PD-1/PD-L1) axis and improve survival in recurrent, metastatic, and locally advanced HNSCC. Tumor cells produced exosomes directly suppress cytotoxic T-lymphocytes activity by modulating immune checkpoint pathways and disrupting T-cell receptor signaling. Cancer-associated fibroblast-derived exosomes (CAF-Exos) function indirectly by conditioning immune escape and tumor growth. Together, these exosomal populations cooperate to create an immunosuppressive niche that hinders the efficacy of immunotherapies. CAF-Exos induce TME changes that exclude CD8⁺ T-cells, promote regulatory T-cells (Tregs), and upregulate PD-L1 expression in tumor cells. The bidirectional transfer of microRNAs (miRNAs) between tumor cells and CAFs enhances epithelial–mesenchymal transition (EMT), suppresses cytotoxic lymphocytes, and undermines ICI efficacy. This review article summarizes recent publications about plasma-derived exosomes from HNSCC patients. These exosomes carry tumor and immune checkpoint markers, reflect tumor burden and treatment response, and strongly modulate immune cells by suppressing T- and B-cell activity and promoting immunosuppressive macrophages. We encourage functional and biomechanistic future studies in the field of HNSCC that examine how CAF subtypes exosomes achieve an immunoresistant TME. Full article

The pivotal role of reactive oxygen species (ROS), especially peroxides, in multiple cell signalling pathways has been well-established. Superoxide dismutase 1 (SOD-1) represents a major intracellular source of hydrogen peroxide. Antigen-dependent activation of human T lymphocytes has been previously described by us to induce both SOD-1 production and secretion by T cells. SOD-1 mediated pathways have also been described to deliver proinflammatory signals and to affect the differentiation of immune-suppressor subsets (Treg). The mechanisms underlying extracellular SOD-1 export by activated T cells remain largely undefined. Indeed, SOD-1, like the leaderless proteins, is unable to exploit the conventional trans-Golgi vesicular secretion pathway. Here, we propose that ABCA1 transporters play a role in the mechanisms underlying SOD-1 secretion by activated T cells. Indeed, ABC transporter inhibition by using glyburide significantly decreases SOD-1 secretion by antigen-triggered human T cells in vitro. The effect has been confirmed by using four different detection techniques, as represented by Western blotting, ELISA, flow cytometry and confocal microscopy. Collectively, our findings indicate that ABCA1 transporter-dependent secretion supports the vesicular secretory machinery and might contribute to the extracellular release of SOD-1 by activated T cells. This mechanism highlights ABCA1 as a promising molecular target for therapeutic modulation of deranged immune activation. Full article

Inflammatory bowel disease (IBD) is a chronic condition whose pathogenesis is not entirely clear. Impaired immune regulation has been hypothesized as the mechanism responsible for the abnormal response of adoptive immunity to enteric microbial antigens. Regulatory T cells (Tregs) have been regarded as the crucial element of immune regulation, since the discovery that humans lacking Tregs due to mutation of FOXP3 develop autoimmune disorders, including severe bowel inflammation. The existing publications concerning T regulatory cells in human IBD have been reviewed, and current evidence does not clearly indicate quantitative disturbances or functional defects of Tregs in human inflammatory bowel disease. The possible mechanisms explaining immunoregulatory failure in IBD have been summarized. So far, only one clinical trial with Tregs infusion has been completed, and its results do not provide sufficient data on the efficacy or safety of Tregs-based therapies in IBD. It will probably be difficult to implement them in clinical practice in the near future. Full article

Hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC) are highly lethal cancers marked by profound epigenetic and metabolic reprogramming. Among the candidate biomarkers, the DNA methyltransferase DNMT3A and the guanine monophosphate synthetase (GMPS) have emerged as potential prognostic drivers, yet their roles across tumor contexts remain unclear. Here, we demonstrate the application of KMplotter to interrogated pan-cancer transcriptomic and survival datasets encompassing over 7000 patients, complemented by expression profiling of normal, tumor, and metastatic tissues, and integrated tumor microenvironment (TME) analyses. Elevated DNMT3A and GMPS expression correlated with worse overall survival in HCC, particularly in Asian patients, while in PDAC, high DNMT3A but low GMPS expression predicted favorable outcomes. Both genes were consistently upregulated in tumors relative to normal tissues, with further increases in metastatic HCC. Immune deconvolution revealed that DNMT3A was linked to Th2/Treg-enriched niches, whereas GMPS overexpression coincided with high mutational burden or stromal enrichment, fostering immunosuppressive microenvironments. Comparative analysis of toll-like receptor signatures highlighted divergent antigen-sensing pathways, with HCC reflecting viral-driven immune exhaustion and PDAC showing self-antigen–associated signaling. Collectively, these findings position DNMT3A and GMPS as context-dependent biomarkers that integrate metabolic and immune cues to shape prognosis in liver and pancreatic cancer, offering mechanistic insight and translational relevance for patient stratification. Full article

Objective: This study investigated whether rapamycin could modulate the polarisation of CD4+ T cells towards T_H1, T_H2, T_H17, and Treg cells using peripheral blood mononuclear cell (PBMC) obtained from patients with granulomatosis with polyangiitis and microscopic polyangiitis (GPA/MPA). Methods: Twenty patients with GPA/MPA were included in this study. Their stored PBMCs were cultured and stimulated with anti-CD3 and anti-CD28 antibodies for 72 h in the presence or absence of rapamycin (10 nM). The cells were stained for surface markers with anti-CD4-FITC and anti-CD25-APC, followed by intracellular staining using anti-interferon (IFN)-γ-PE, anti-IL-4-PerCP-Cy5, anti-IL17A-APC, and anti-Foxp3-PE. The stained cells were analysed using a flow cytometer. Results: The median age of the 20 GPA/MPA patients (10 men and 10 women) was 65.5 years. Rapamycin treatment significantly modulated the polarisation of CD4+IFN-γ+ T (T_H1) cells compared to no treatment among GPA/MPA patients. In addition, the polarisation of CD4+IFN-γ+ T (T_H1) cells was also significantly reduced in rapamycin-treated PBMC obtained from active patients compared to untreated PBMC from the same patients; however, these alterations were not observed in inactive patients. Conversely, rapamycin treatment did not affect the polarisation of CD4+IL-4+ T (T_H2), CD4+IL-17+ T (T_H17), or CD4+FoxP3+CD25+ T (Treg) cells, regardless of GPA/MPA activity. Conclusions: This study was the first pilot study to demonstrate that rapamycin modulates the polarisation of CD4+ T cells towards CD4+IFN-γ+ T cells in active GPA/MPA. Full article

Background/Objectives: Acute pneumonia remains one of the leading causes of mortality worldwide. The pathogenesis of the disease is determined by the nature of the host immune response. The balance between effector and regulatory T cells (Treg) is critical, as it determines the severity of inflammation and the regenerative capacity of lung tissue. The development of new approaches to modulate the immune response using promising synthetic compounds opens up the possibility of targeted cytokine balance restoration of cytokine balance and Tregs functions This study investigated the effects of the newly synthesized complex of 1-(2-Ethoxypropyl)-4-(pent-1-yn-1-yl)piperidin-4-yl Propionate with β-Cyclodextrin (MXF-22), on the populations of CD4⁺, CD4⁺CD25⁺ and CD4⁺FoxP3⁺ T cells in an oleic acid-induced acute lung injury rat model. Methods: Quantitative analysis of CD4⁺, CD4⁺CD25⁺, and CD4⁺FoxP3⁺ T cell subsets and serum IL-4 and TGF-β levels were determined by flow cytometry and ELISA assays, respectively. Results: The study revealed a significant decrease in the number of CD4⁺ T cells and their regulatory subsets (CD4⁺CD25⁺, CD4⁺FoxP3⁺) during acute pneumonia. Oral administration of MXF-22 contributed to a pronounced recovery of these parameters, accompanied by increased levels of IL-4 and TGF-β, which indicated the activation of anti-inflammatory and reparative processes. Conclusions: MXF-22 showed a pronounced immunomodulatory effect contributing to the restoration of the function of CD4⁺ FoxP3⁺ T regs in acute pneumonia rat model. Full article

Radiopharmaceutical therapy (RPT) offers tumor-selective radiation delivery and represents a promising platform for combination with immune checkpoint inhibitors (ICIs). While prior studies suggest that RPT can stimulate antitumor immunity, synergy with ICIs may depend on radionuclide properties, absorbed dose, and radiation distribution within the tumor microenvironment. This study evaluated how radionuclide selection and dose influence immune stimulation and therapeutic efficacy of GD2-targeted antibody-based RPT combined with ICIs. Dinutuximab, an anti-GD2 monoclonal antibody, was radiolabeled with β⁻-emitters (⁹⁰Y, ¹⁷⁷Lu) or an α-emitter (²²⁵Ac). C57Bl6 mice bearing GD2⁺ tumors received 4 or 15 Gy tumor-absorbed doses, determined by individualized dosimetry, with or without dual ICIs (anti-CTLA-4 and anti-PD-L1). In vivo imaging, ex vivo biodistribution, survival, histological, and gene expression analyses were performed to assess therapeutic and immunological outcomes. All radiolabeled constructs demonstrated preferential uptake in GD2⁺ tumors. Combination therapy improved survival in a radionuclide- and dose-dependent manner, with the greatest benefit in the ²²⁵Ac + ICI group at 15 Gy. Treatment activated type I interferon signaling and increased MHC-I and PD-L1 expression. Notably, ⁹⁰Y reduced regulatory T cells, enhancing CD8⁺/Treg ratios, while ²²⁵Ac induced robust interferon-driven activation. Radionuclide selection and absorbed dose critically shape immune and therapeutic outcomes of antibody-based RPT combined with ICIs, underscoring the importance of delivery mechanism and dose optimization in combination therapy strategies. Full article

High mobility group A1 (HMGA1) is a chromatin-associated protein that regulates transcription and drives cancer progression. In this pan-cancer study, we analyzed multi-omics data to comprehensively characterize HMGA1’s expression patterns, prognostic significance, epigenetic regulation, and immunotherapy roles. We found that HMGA1 was markedly upregulated in most cancers, mainly driven by promoter hypomethylation and copy number alterations. Elevated HMGA1 expression was consistently associated with unfavorable patient survival, stemness features, and the activation of oncogenic signaling pathways. Crucially, HMGA1 expression correlated with an immune-excluded tumor microenvironment, characterized by suppressed stromal and immune scores. Even in tumors with immune infiltration, high HMGA1 predicted poor prognosis, likely mediated by enhanced regulatory T-cell (Treg) recruitment and impaired effector immune function. Moreover, HMGA1 levels were positively correlated with tumor mutational burden (TMB), and microsatellite instability (MSI), and immunotherapy-related checkpoints including PD-1, CTLA-4, and TIGIT. Drug sensitivity analysis further revealed that HMGA1 predicted resistance to AKT inhibitors, which was experimentally validated in breast cancer cells treated with Capivasertib. Collectively, our findings establish HMGA1 as a pivotal oncogenic regulator and a promising biomarker for prognosis and for guiding strategies in immunotherapy and overcoming targeted therapy resistance. Full article