Search Results (6,683)

In today’s oncology, immunotherapy arises as a potent complement for conventional cancer treatment, allowing for obtaining better patient outcomes. B7-H3 (CD276) is a member of the B7 protein family, which emerged as an attractive target for the treatment of various tumors. The molecule modulates anti-cancer immune responses, acting through diverse signaling pathways and cell populations. It has been implicated in the pathogenesis of numerous malignancies, including melanoma, gliomas, lung cancer, gynecological cancers, renal cancer, gastrointestinal tumors, and others, fostering the immunosuppressive environment and marking worse prognosis for the patients. B7-H3 targeting therapies, such as monoclonal antibodies, antibody–drug conjugates, and CAR T-cells, present promising results in preclinical studies and are the subject of ongoing clinical trials. CAR-T therapies against B7-H3 have demonstrated utility in malignancies such as melanoma, glioblastoma, prostate cancer, and RCC. Moreover, ADCs targeting B7-H3 exerted cytotoxic effects on glioblastoma, neuroblastoma cells, prostate cancer, and craniopharyngioma models. B7-H3-targeting also delivers promising results in combined therapies, enhancing the response to other immune checkpoint inhibitors and giving hope for the development of approaches with minimized adverse effects. However, the strategies of B7-H3 blocking deliver substantial challenges, such as poorly understood molecular mechanisms behind B7-H3 protumor properties or therapy toxicity. In this review, we discuss B7-H3’s role in modulating immune responses, its significance for various malignancies, and clinical trials evaluating anti-B7-H3 immunotherapeutic strategies, focusing on the clinical potential of the molecule. Full article

Highly pathogenic avian influenza (HPAI) remains a persistent threat to global poultry production and public health. Current vaccine platforms show limited cross-clade efficacy and often fail to induce mucosal immunity. Recent advances in microbiome research reveal critical roles for gut commensals in modulating vaccine-induced immunity, including enhancement of mucosal IgA production, CD8⁺ T-cell activation, and modulation of systemic immune responses. Engineered commensal bacteria such as Lactococcus lactis, Bacteroides ovatus, Bacillus subtilis, and Staphylococcus epidermidis have emerged as promising live vectors for antigen delivery. Postbiotic and synbiotic strategies further enhance protective efficacy through targeted modulation of the gut microbiota. Additionally, artificial intelligence (AI)-driven tools enable predictive modeling of host–microbiome interactions, antigen design optimization, and early detection of viral antigenic drift. These integrative technologies offer a new framework for mucosal, broadly protective, and field-deployable vaccines for HPAI control. However, species-specific microbiome variation, ecological safety concerns, and scalable manufacturing remain critical challenges. This review synthesizes emerging evidence on microbiome–immune crosstalk, commensal vector platforms, and AI-enhanced vaccine development, emphasizing the urgent need for One Health integration to mitigate zoonotic adaptation and pandemic emergence. Full article

The prostate gland, a male accessory reproductive organ, is regulated by hormonal inputs and autonomic innervation from the major pelvic ganglion. This study examined the effects of major pelvic ganglion denervation on prostate histology, immune cell infiltration, and systemic levels of prolactin, testosterone, and cytokines in rats. Male Wistar rats (300–350 g) were divided into groups receiving bilateral axotomy of the hypogastric nerve, the pelvic nerve, or both, alongside with a sham-operated control. After 15 days, the animals were killed, and prostate tissue was dissociated in DMEM medium containing DNase I and collagenase. The dissociated cells were stained with fluorochrome-conjugated antibodies, and cell characterization was performed using a flow cytometer. Hematoxylin and eosin (H&E) staining was used to analyze histological characteristics, while testosterone, prolactin, and interleukin levels were measured via ELISA. Histological analysis revealed inflammatory atypical hypertrophy e hiperplasia. Immunological assessments demonstrated increased leukocytes, T lymphocytes (CD4⁺ and CD8⁺), B lymphocytes, and macrophages following double nerve axotomy. Serum analyses showed elevated pro-inflammatory cytokines IL-1β, IL-6, and IFN-γ, as well as anti-inflammatory IL-10, in denervated animals. Hormonal assessments revealed significant increases in serum prolactin and testosterone levels after double axotomy. Loss of neural control may promote pathological prostate changes via inflammation and hormonal dysregulation, offering insights into neuroimmune and neuroendocrine mechanisms underlying prostate pathologies. Full article

Multiple myeloma (MM) is predominantly a disease of the elderly. In recent years, a surge of highly effective plasma cell therapies has revolutionized the care of elderly multiple myeloma (MM) patients, for whom frailty and age-related competing causes of mortality determine management. Traditionally, the treatment of newly diagnosed elderly patients has centered on doublet or triplet combinations composed of immunomodulators (IMIDs), proteasome inhibitors (PIs), anti-CD38 monoclonal antibodies (mAbs), and corticosteroids producing median progression-free survival (PFS) rates between 34 and 62 months. However, recently, a series of large phase III clinical trials examining quadruplet regimens of PIs, IMIDs, corticosteroids, and anti-CD38 mAbs have shown exceptional outcomes, with median PFS exceeding 60 months, albeit with higher rates of peripheral neuropathy (≥Grade 2: 27% vs. 10%) when PIs and IMIDs are combined, and infections (≥Grade 3: 40% vs. 29–41%) with the addition of anti-CD38mAbs. The development of T-cell redirecting therapies including T-cell engagers (TCEs) and CAR-T cells has further expanded the therapeutic arsenal. TCEs have shown exceptional activity in relapsed disease and are being explored in the newly diagnosed setting with promising early results. However, concerns remain regarding the logistical challenges of step-up dosing, which often necessitates inpatient admission, the infectious risks, and the financial burden associated with TCEs in elderly patients. CAR-T, the most potent commercially available therapy for MM, offers the potential of a ‘one and done’ approach. However, its application to elderly patients has been tempered by significant concerns of cytokine release syndrome, early and delayed neurological toxicity, and its overall tolerability in frail patients. Robust data in frail patients are still needed. How CAR-T and TCEs will be sequenced among the growing therapeutic armamentarium for elderly MM patients remains to be determined. This review explores the safety, efficacy, cost, and logistical barriers associated with the above treatments in elderly MM patients. Full article

Human leukocyte antigen class I (HLA-I) molecules present intracellular peptides on the cell surface to enable CD8+ T cells to effectively control viral infections. Many viruses disrupt this antigen presentation pathway to evade immune detection. In this study, we demonstrate that SARS-CoV-2 Nsp1 impairs both the constitutive and interferon-γ (IFN-γ)-induced upregulation of HLA-I. Moreover, Nsp1 also blocks IFN-γ-induced expression of HLA-II. We found that, contrary to previously published work, the early SARS-CoV-2 B 1.1.7 Alpha variant lacking the accessory protein ORF8 retained full capacity to downregulate HLA-I, comparable to an ORF8-expressing wild-type isolate. While ectopic overexpression of ORF8 could reduce HLA-I surface levels, this effect was only observed at high expression levels. In contrast, moderate expression of the viral protein Nsp1 was sufficient to potently suppress both basal and IFN-γ-induced HLA-I, as well as HLA-II expression. To probe the underlying mechanism, we analyzed HLA-I-associated genes in previously published RNA-sequencing datasets and confirmed that Nsp1 reduces expression of components required for HLA-I biosynthesis and antigen processing. These findings identify Nsp1 as a key factor that impairs antigen presentation pathways, potentially contributing to the ability of SARS-CoV-2 to modulate immune recognition. Full article

The high incidence of melanoma leading to a poor prognosis rate endorses the development of alternative and innovative approaches in the treatment of melanoma. Therefore, the present study aims to develop and characterize, in terms of physicochemical features and biological impact, an aqueous suspension of magnetite (Fe₃O₄) coated with β-cyclodextrin (Fe₃O₄@β-CD) as a potential innovative alternative nanosystem for melanoma therapy. The nanosystem exhibited physicochemical characteristics suitable for biological applications, revealing a successful complexation of Fe₃O₄ NPs with β-CD and an average size of 18.1 ± 2.1 nm. In addition, the in vitro evaluations revealed that the newly developed nanosystem presented high biocompatibility on a human keratinocyte (HaCaT) monolayer and selective antiproliferative activity on amelanotic human melanoma (A375) cells, inducing early apoptosis features when concentrations of 10, 15, and 20 μg/mL were employed for 48 h and 72 h. Collectively, the Fe₃O₄@β-CD nanosystem reveals promising features for an adjuvant approach in melanoma treatment, mainly due to its β-cyclodextrin coating, thus endorsing a potential co-loading of therapeutic drugs. Furthermore, the intrinsic magnetic core of Fe₃O₄ NPs supports the magnetically based cancer treatment strategies. Full article

Treatment-resistant depression (TRD) is associated with immune dysregulation. Ketamine, a rapid-acting antidepressant, may exert effects via immunomodulation. The aim was to examine ketamine’s impact on immune markers in TRD, including T-cell subsets, cytokines, and in vitro T-cell responses. Eighteen TRD inpatients received 0.5 mg/kg iv ketamine. Blood was sampled at baseline, 4 h, and 24 h to analyze T-cell phenotypes (CD28, CD69, CD25, CD95, HLA-DR) and serum cytokines (IL-6, IL-8, IL-10, TNF-α, IL-1β, IL-12p70). In vitro, PBMCs from TRD patients and controls were exposed to low (185 ng/mL) and high (300 ng/mL) ketamine doses. Ketamine induced a transient increase in total T cells and CD4⁺CD25⁺ and CD4⁺CD28⁺ subsets at 4 h, followed by a reduction in CD4⁺ and an increase in CD8⁺ T cells at 24 h, decreasing the CD4⁺/CD8⁺ ratio. Activation markers (CD4⁺CD69⁺, CD4⁺HLA-DR⁺, CD8⁺CD25⁺, CD8⁺HLA-DR⁺) declined at 24 h. Serum IL-10 increased, IL-6 decreased, and IL-8 levels—initially elevated—showed a sustained reduction. In vitro, high-dose ketamine enhanced the proliferation of TRD CD4⁺ T cells and dose-dependent IL-8 and IL-6 secretion from activated cells. Ketamine induces rapid, transient immune changes in TRD, including reduced T-cell activation and cytokine modulation. A sustained IL-8 decrease suggests anti-inflammatory effects and potential as a treatment-response biomarker. Full article

Background/Objectives: While ART effectively suppresses HIV viremia, many PLWH exhibit persistent immune dysfunction. This study aimed to assess immune recovery and immune exhaustion (PD-1/PD-L1 expression) in newly diagnosed versus long-term ART-treated individuals. Methods: We analyzed 79 PLWH: 52 newly diagnosed individuals (12-month follow-up) and 27 long-term-treated patients (Ukrainian refugees). Flow cytometry was used to evaluate CD4+ and CD8+ counts, the CD4+/CD8+ ratio, and PD-1/PD-L1 expression on CD3+, CD4+, and CD19+ lymphocytes. ART regimen and HIV subtype were included as covariates in linear regression models. Results: At 12 months, CD4+ counts were similar between groups (median 596.5 vs. 621 cells/μL, p = 0.22), but newly diagnosed patients had higher CD8+ counts (872 vs. 620 cells/μL, p = 0.028) and a lower CD4+/CD8+ ratio (0.57 vs. 1.05, p = 0.0027). Immune exhaustion markers were significantly elevated in newly diagnosed individuals: CD4+ PD-1+ T cells (24.4% vs. 3.85%, p = 0.0002) and CD3+ PD-1+ T cells (27.3% vs. 12.35%, p < 0.0001). Linear regression confirmed group membership independently predicted higher CD3+ (β = +21.92, p < 0.001), CD4+ (β = +28.87, p < 0.0001), and CD19+ (β = +8.73, p = 0.002) percentages. Lipid parameters and SCORE2 did not differ significantly. Conclusions: Despite virologic suppression and CD4+ recovery, immune exhaustion markers remain elevated in newly diagnosed PLWH, suggesting incomplete immune normalization. Traditional parameters (CD4+ count and CD4+/CD8+ ratio) may not fully capture immune status, warranting broader immunologic profiling in HIV care. Full article

Avian influenza A viruses (IAVs) pose a persistent threat to the poultry industry, causing substantial economic losses. Although traditional vaccines have helped reduce the disease burden, they typically rely on multivalent antigens, emphasize humoral immunity, and require intensive production. This study aimed to establish a genetically matched host–cell system to evaluate antigen-specific immune responses and identify conserved CD8+ T cell epitopes in avian influenza viruses. To this end, we developed an MHC class I genotype (B21)-matched host (Lohmann VALO SPF chicken) and cell vector (DF-1 cell line) model. DF-1 cells were engineered to express the hemagglutinin (HA) gene of clade 2.3.4.4b H5N1 either transiently or stably, and to stably express the matrix 1 (M1) and nucleoprotein (NP) genes of A/chicken/South Korea/SL20/2020 (H9N2, Y280-lineage). Following prime-boost immunization with HA-expressing DF-1 cells, only live cells induced strong hemagglutination inhibition (HI) and virus-neutralizing (VN) antibody titers in haplotype-matched chickens. Importantly, immunization with DF-1 cells transiently expressing NP induced stronger IFN-γ production than those expressing M1, demonstrating the platform’s potential for differentiating antigen-specific cellular responses. CD8+ T cell epitope mapping by mass spectrometry identified one distinct MHC class I-bound peptide from each of the HA-, M1-, and NP-expressing DF-1 cell lines. Notably, the identified HA epitope was conserved in 97.6% of H5-subtype IAVs, and the NP epitope in 98.5% of pan-subtype IAVs. These findings highlight the platform’s utility for antigen dissection and rational vaccine design. While limited by MHC compatibility, this approach enables identification of naturally presented epitopes and provides insight into conserved, functionally constrained viral targets. Full article

Histotripsy is a novel, noninvasive, non-thermal technology invented in 2004 for the precise destruction of biologic tissue. It offers a powerful alternative to more conventional thermal or surgical interventions. Using short-pulse, low-duty cycle ultrasonic waves, histotripsy creates cavitation bubble clouds that selectively and precisely destroy targeted tissue in a predefined volume while sparing critical structures like bile ducts, ureters, and blood vessels. Such precision is of value when treating tumors near vital structures. The FDA has cleared histotripsy for the treatment of all liver tumors. Major medical centers are currently spearheading clinical trials, and some institutions have already integrated the technology into patient care. Histotripsy is now being studied for a host of other cancers, including primary kidney and pancreatic tumors. Preclinical murine and porcine models have already revealed promising outcomes. One of histotripsy’s primary advantages is its non-thermal mechanical actuation. This feature allows it to circumvent the limitations of heat-based techniques, including the heat sink effect and unpredictable treatment margins near sensitive tissues. In addition to its non-invasive ablative capacities, it is being preliminarily explored for its potential to induce immunomodulation and promote abscopal inhibition of distant, untreated tumors through CD8+ T cell responses. Thus, it may provide a multilayered therapeutic effect in the treatment of cancer. Histotripsy has the potential to improve precision and outcomes across a multitude of specialties, from oncology to cardiovascular medicine. Continued trials are crucial to further expand its applications and validate its long-term efficacy. Due to the speed of recent developments, the goal of this review is to provide a comprehensive and updated overview of histotripsy. It will explore its physics-based mechanisms, differentiating it from similar technologies, discuss its clinical applications, and examine its advantages, limitations, and future. Full article

Whether the spongiotic reaction caused by the interaction of keratinocytes, T-lymphocytes, inflammatory dendritic epidermal cells (IDECs), and Langerhans cells (LCs) observed in atopic dermatitis (AD) represents a common feature of spongiosis in various skin diseases remains unclear. We analyzed the characteristics of spongiosis in AD compared with those in other eczematous dermatitis and inflammatory skin diseases by using immunohistochemical methods. Infiltration of IDECs (CD11c+ cells and/or CD206+ cells) and T-lymphocytes, accompanied by degenerated keratinocytes and aggregated LCs (CD207+ cells), was frequently observed as a common feature of spongiosis in multiple conditions. However, IDECs expressing IgE were identified exclusively in IgE-mediated AD. Aggregation of IDECs was predominantly observed in the spongiosis of adaptive immune-mediated eczematous disorders, such as AD and allergic contact dermatitis. These IDEC aggregations constituted the major components of the epidermal dendritic cell clusters seen in AD and other eczematous or eczematoid dermatoses, and may serve as a useful distinguishing marker from Pautrier collections seen in cutaneous T-cell lymphoma. These findings suggest that IDECs, in cooperation with other immune cells, may play a pivotal role in spongiosis formation in AD and various skin diseases, although the underlying immunopathological mechanisms differ among these conditions. Full article

Accounting for 15–30% of colorectal cancer cases, the serrated pathway remains poorly characterized compared to the adenoma–carcinoma sequence. It involves sessile serrated lesions as precursors and is characterized by BRAF mutations (BRAF^V600E), CpG island hypermethylation, and microsatellite instability (MSI). Using label-free proteomics, we compared normal tissue margins from patients with diverticular disease, sessile serrated lesions, low-grade adenomas, and high-grade adenomas. We identified S100A14 as significantly overexpressed in sessile serrated lesions compared to low-grade adenomas, high-grade adenomas, and normal tissues. This overexpression was confirmed by immunohistochemical scoring in an independent cohort. Gene expression analyses of public datasets showed higher S100A14 expression in BRAF^V600E-mutated and MSI-H colorectal cancers compared to microsatellite stable BRAF^wt tumors. This finding was confirmed by immunohistochemical scoring in an independent colorectal cancer cohort. Furthermore, single-cell RNA sequencing analysis from the Human Colon Cancer Atlas revealed that S100A14 expression in tumor cells positively correlated with the abundance of tumoral CD8⁺ cytotoxic T cells, particularly the CD8⁺ CXCL13⁺ subset, known for its association with a favorable response to immunotherapy. Collectively, our results demonstrate for the first time that S100A14 is a potential biomarker of serrated neoplasia and further suggests its potential role in predicting immunotherapy responses in colorectal cancer. Full article

Systemic lupus erythematosus (SLE) is a severe autoimmune disease characterized by autoantibody production and multi-organ involvement. Anifrolumab, a monoclonal antibody targeting the type I interferon (IFN) receptor, has been approved for the treatment of SLE. Our aim was to investigate the long-term effects of inhibited type I IFN signaling on circulating follicular helper T subsets (T_FH), follicular regulatory T cells (T_FR), and B lymphocyte subpopulations, reflecting the ongoing germinal center reactions in SLE patients. Peripheral blood samples were obtained from ten SLE patients before the initiation of anifrolumab treatment, and at months 6 and 12 of the intervention period. Flow cytometry analysis was performed to assess the frequencies of circulating T_FH cell subsets, T_FR cells, and certain B cell subpopulations. Serological parameters, including autoantibody levels and complement components, were determined as part of the routine diagnostic evaluation. We observed a significant and sustained reduction in the percentage of activated circulating T_FH cells. Notably, the frequency of CXCR3⁻CCR6⁺ T_FH17 cells decreased, whereas the proportion of CXCR3⁺CCR6⁻ T_FH1 cells increased significantly. Furthermore, the proportion of the IgD⁻CD27⁻ double-negative B lymphocytes was also significantly reduced. These findings suggest that anifrolumab therapy attenuates T_FH cell activation, which may contribute to its clinical efficacy by modulating germinal center responses in SLE. Full article

Background/Objectives: Brain metastasis (BM) is a common and often early manifestation in lung adenocarcinoma (LUAD), yet its tumor microenvironment remains poorly defined at the time of initial diagnosis. This study aims to characterize early immune microenvironmental alterations in synchronous BM using spatial proteomic profiling. Methods: We performed digital spatial proteomic profiling using the NanoString GeoMx platform on formalin-fixed paraffin-embedded tissues from five treatment-naïve LUAD patients in whom BM was the initial presenting lesion. Paired primary lung and brain metastatic samples were analyzed across tumor and stromal compartments using 68 immune- and tumor-related protein markers. Results: Spatial profiling revealed distinct expression patterns between primary tumors and brain metastases. Immune regulatory proteins—including IDO-1, PD-1, PD-L1, STAT3, PTEN, and CD44—were significantly reduced in brain metastases (p < 0.01), whereas pS6, a marker of activation-induced T-cell death, was significantly upregulated (p < 0.01). These alterations were observed in both tumor and stromal regions, suggesting a more immunosuppressive and apoptotic microenvironment in brain lesions. Conclusions: This study provides one of the first spatially resolved proteomic characterizations of synchronous BM at initial LUAD diagnosis. Our findings highlight early immune escape mechanisms and suggest the need for site-specific immunotherapeutic strategies in patients with brain metastasis. Full article

FMC63-CAR T cell therapy targeting CD19 protein on malignant B-cells is effective in patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL), with complete response rates of 43–54%. Common germline variants of the immune-checkpoint regulator CTLA-4 may elicit different responses to CAR-T cell therapy. The CTLA4 gene single-nucleotide polymorphism rs231775 coding threonine or alanine at amino acid position 17 of the CTLA-4 protein was prevalent in 55% of the studied DLBCL patients. In a retrospective comparative analysis of clinical outcome, there were significant differences in CTLA4 A17hom vs. T17Ahet and T17hom carriers with four-year progression-free survival at 77%, 59%, and 30% (p = 0.019), four-year overall survival was 79%, 41%, and 33% (p = 0.049), the relapse rates were 20%, 37%, and 56% (p = 0.025), and the death rates 20%, 54%, and 52% (p = 0.049). Conclusions: CTLA4 rs231775 polymorphism may impact the treatment outcome in FMC63-anti-CD19 CAR-T cell therapy, with an association of the CTLA4 minor allele A17 to favorable treatment outcome. Full article