Search Results (2,014)

Background: Successful translation of cancer immunotherapy is underscored by the efficacy of PD-1/PD-L1 and CTLA-4 inhibitors in the treatment of various malignancies. However, their limited efficacy in glioma indicates alternative immune escape mechanisms. We investigated B and T Lymphocyte Attenuator (BTLA), a co-inhibitory receptor structurally and functionally analogous to PD-1, to determine if it constitutes a key, unaddressed mechanism of immune escape and a novel therapeutic target in glioma. Methods: We analyzed BTLA expression and function within the tumor microenvironment of a Moroccan cohort (n = 44). This was complemented by multiparameter flow cytometry on peripheral blood from glioblastoma (GBM) patients (n = 8) to assess circulating T cell profiles. Findings were corroborated using independent transcriptomic datasets from TCGA and CGGA cohorts. Single-cell RNA-seq and citeSeq identified specific BTLA-expressing cell populations. Results: Elevated BTLA expression was significantly associated with aggressive features and poor overall survival in glioma patients. Mechanistically, BTLA levels were positively correlated with pro-tumorigenic factors, immune infiltration, and immunosuppressive checkpoints. Single-cell and citeSeq analyses revealed that BTLA was primarily expressed by exhausted T cells and conventional type 1 dendritic cells (cDC1) within the GBM microenvironment. Crucially, this phenotype was translated systemically; BTLA defined dysfunctional circulating CD8⁺ and CD4⁺ T cells characterized by diminished IFN-γ production, alongside reduced granzyme B and perforin in CD8⁺ T cells. Conclusions: Our findings indicate that BTLA may represent a relevant pathway associated with an immunosuppressive glioma microenvironment. The therapeutic potential of targeting this pathway, particularly in combination with PD-1/PD-L1 blockade, warrants further investigation. Full article

Residual inflammation remains a hallmark of treated HIV infection despite durable viral suppression. Whether previous SARS-CoV-2 infection is associated with residual inflammation in people living with HIV (PLWH) remains incompletely understood. This study evaluated the association between previous COVID-19 and persistent inflammation in virally suppressed PLWH. In this retrospective observational single-center study, 286 adults receiving antiretroviral therapy between January 2023 and December 2025 were included. Patients were stratified according to documented SARS-CoV-2 infection history. A secondary analysis included 231 individuals with sustained viral suppression (HIV-RNA < 50 copies/mL). Inflammatory biomarkers, immune recovery parameters, metabolic characteristics, and independent predictors of elevated inflammatory biomarker levels were evaluated. Previous SARS-CoV-2 infection was associated with significantly higher concentrations of C-reactive protein, interleukin-6, tumor necrosis factor-α, erythrocyte sedimentation rate, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio (all p< 0.01). Among virally suppressed patients, elevated inflammatory biomarker levels were associated with lower CD4+ T-cell counts, lower CD4/CD8 ratios, obesity, metabolic syndrome, dyslipidemia, and hepatic steatosis. Previous SARS-CoV-2 infection, obesity, metabolic syndrome, and CD4+ T-cell counts <500 cells/mm³ were independently associated with elevated inflammatory biomarker levels. Previous SARS-CoV-2 infection was independently associated with an unfavorable inflammatory profile in virally suppressed people living with HIV. Given the retrospective observational design, these findings should be interpreted as associations rather than evidence of causality. These findings suggest that long-term host-related and metabolic factors may contribute to residual inflammation beyond viral control and highlight the need for prospective studies investigating strategies to reduce residual immune activation in treated HIV infection. Full article

Global elimination of hepatitis C virus (HCV) infection requires not only direct-acting antivirals (DAAs) but also the development of a highly effective prophylactic and/or therapeutic vaccine. Background/Objectives: Our aim was to optimize the composition of the candidate vaccine against HCV by combining recombinant non-structural proteins and a DNA construct with a complex adjuvant. Methods: C57BL/6 and DBA/2J mice were immunized three times at 2-week intervals using different schemes. The viral antigens consisted of a mixture of NS3, NS5A, and NS5B proteins and/or recombinant DNA expressing NS3-NS5B polyprotein. As adjuvants, a complex adjuvant, a mixture of Polymuramil^® and Pyrogenalum^® (NOD1/NOD2 and TLR-4 agonists), or a CpG ODN adjuvant (TLR-9 agonist) were used. Results: The most efficient regimen was three subcutaneous administrations of the combined DNA, recombinant protein components, and a new complex adjuvant. This scheme elicited a robust immune response, characterized by high antibody titers, enhanced antigen-specific lymphocyte proliferation, and significant interferon-gamma (IFN-γ) secretion in both mouse lines. Furthermore, the complex adjuvant outperformed CpG ODN in stimulating both humoral and cellular immunity against the HCV antigens. The vaccine composition stimulated the formation of CD4⁺ memory T cells and decreased the relative frequences of suppressive Treg and MDSCs. Conclusions: The presented candidate vaccine induces a strong immune response to HCV proteins. The next step would be to validate the protective effect in cell culture and animal models. This would one the path to preclinical studies of this vaccine composition. Full article

Background/Objectives: High-grade serous ovarian carcinoma (HGSC) is the most aggressive subtype of epithelial ovarian cancer and is characterized by marked heterogeneity of the tumor immune microenvironment. SET morphology has been associated with homologous recombination deficiency and BRCA1/2 mutations; however, its relationship with the immune microenvironment and progression-free survival (PFS) remains insufficiently understood. This study investigated the association between SET morphology, immune microenvironment characteristics, and PFS in patients with advanced-stage HGSC. Methods: A retrospective cohort of 305 patients with FIGO stage III–IV HGSC treated with primary surgery between 1996 and 2021 was analyzed. Histopathological assessment included evaluation of SET morphology, stromal and intraepithelial tumor-infiltrating lymphocytes (sTILs and itTILs), tumor immune phenotype, and lymphoid aggregates. Immunohistochemical analyses included CD8 and PD-L1 expression. Associations between SET morphology and immune parameters were evaluated using χ² and logistic regression analyses. PFS was assessed using Kaplan–Meier analysis, log-rank testing, and Cox proportional hazards regression. Results: SET morphology was significantly associated with higher sTIL and itTIL levels, increased stromal and intraepithelial CD8⁺ T-cell infiltration, higher PD-L1 TPS and CPS, more frequent primary and secondary lymphoid aggregates, and a predominance of the inflamed immune phenotype (all p < 0.05). Despite these features of an immune-active tumor microenvironment, SET morphology, CD8⁺ T-cell density, PD-L1 expression, lymphoid aggregates, and immune phenotype were not independently associated with prolonged PFS. In contrast, age remained an independent prognostic factor, with patients older than 55 years having a 50% higher risk of disease progression than younger patients (HR = 1.5, 95% CI: 1.1–2.1; p = 0.012). Higher intraepithelial TIL levels (>10%) were independently associated with improved PFS (HR = 2.1, 95% CI: 1.0–4.4; p = 0.045). Conclusions: SET morphology identifies an immune-active subtype of HGSC characterized by increased immune infiltration and PD-L1 expression but does not independently predict prolonged PFS. The dissociation between immune cell abundance and clinical outcome suggests that immune cell functionality, rather than immune infiltration alone, may determine prognosis. Routine histopathological assessment of SET morphology may facilitate biological characterization of HGSC and provide a practical surrogate marker for future biomarker-driven studies evaluating immunotherapy and targeted treatment strategies. Full article

Porcine circovirus type 2 (PCV2) and Mycoplasma hyopneumoniae (Mhp) are major contributors to the porcine respiratory disease complex. Although PCV2-Mhp bivalent inactivated vaccines are useful for simultaneous disease control, their immunogenicity may be improved by adjuvant optimization. This study evaluated a composite adjuvant consisting of porcine interleukin-2 (IL-2), IL-4, IL-6 and MnJ(beta), a colloidal manganese adjuvant, in an initial murine immunogenicity model. Thirty female Kunming mice were assigned to three groups (n = 10/group): bivalent antigen plus IL-2/IL-4/IL-6/MnJ(beta), bivalent antigen plus MnJ(beta), or phosphate-buffered saline. Body weight, complete blood count, peripheral blood T- and B-cell subsets, PCV2-specific IgG and Mhp-specific indirect hemagglutination titers were monitored after primary and booster immunization. The composite formulation did not suppress body-weight gain or induce sustained abnormalities in erythrocyte- or platelet-related indices. WBC, neutrophil, lymphocyte and monocyte counts were elevated in group A at days 7 and 28 post-primary immunization, indicating transient immune activation. Day-56 flow cytometry indicated increased CD19+IgM-IgD- B-cell and effector/memory T-cell-associated responses. PCV2-specific IgG increased from day 14 onward. At day 56, the OD450 value in group A reached 1.532 ± 0.006, compared with 1.095 ± 0.004 in group C1 and 0.102 ± 0.002 in group C2, corresponding to approximately 1.40-fold and 15.09-fold higher levels than the MnJ(beta)-adjuvanted and PBS control groups, respectively. Mhp-specific IHA titers were also maintained at high levels after booster immunization; at day 56, group A showed a log2 endpoint titer of 13.00 ± 0.00, corresponding to a GMT of 1:8192, whereas group C1 showed a log2 endpoint titer of 12.00 ± 0.00, corresponding to a GMT of 1:4096, and group C2 remained negative. These results indicate that the IL-2/IL-4/IL-6/MnJ(beta) composite adjuvant demonstrates potential for improving antibody and peripheral lymphocyte responses to PCV2-Mhp bivalent antigen, but protective efficacy must be confirmed in target-species challenge studies. Full article

Halo nevus (HN), also known as Sutton nevus or leukoderma acquisitum centrifugum, is a melanocytic lesion characterized by a depigmented halo surrounding a central nevus. Although HN is a benign dermatological condition, increasing evidence indicates that HN represents a dynamic in vivo model of melanocyte-directed immune response with relevant implications for autoimmunity, pigmentary disorders, melanoma regression, and tumor immunosurveillance. The pathogenesis is primarily mediated by CD8+ cytotoxic T lymphocytes via interferon-γ-driven pathways, leading to targeted destruction of melanocytes. However, recent studies have highlighted the importance of immune regulatory mechanisms, including PD-L1-expressing neutrophils and FOXP3+ regulatory T cells, which limit excessive immune-mediated damage and may contribute to the self-limited course and repigmentation observed in some lesions. Additional cytotoxic mediators, particularly granulysin, appear to strengthen melanocyte-directed cytotoxicity, while dendritic cells, macrophages, Langerhans cells, neutrophils, and natural killer cells contribute to antigen presentation, tissue remodeling, and immune resolution. HN shares key immunopathogenic features with vitiligo and melanoma regression but differs from both conditions due to its localized, tightly regulated behavior. Moreover, the halo phenomenon is not restricted to melanocytic lesions, supporting the view that it reflects a broader immune pattern rather than a disease-specific entity. This review provides a comprehensive synthesis of the clinical, histopathological, immunological, diagnostic, and translational aspects of halo nevus. Based on the available evidence, we propose a self-limited melanocyte autoimmunity model to explain the characteristic balance between melanocyte destruction, immune regulation, and spontaneous resolution observed in halo nevi. Full article

Background: Alternative immune checkpoints such as lymphocyte-activation gene 3 (LAG-3), T-cell immunoglobulin and mucin-domain-containing-3 (TIM-3), and V-domain Ig suppressor of T-cell activation (VISTA) have emerged as potential modulators of tumor immune escape. However, their expression patterns and prognostic significance in advanced laryngeal squamous cell carcinoma (LSCC) remain insufficiently characterized. This study aimed to evaluate LAG-3, TIM-3, and VISTA expression on tumor-infiltrating lymphocytes (TILs), examine their association with CD8+ TIL density and clinicopathological features, and determine their impact on survival outcomes. Methods: In this retrospective observational cohort study, 132 patients who underwent total or partial laryngectomy for stage III–IV LSCC were included. Tissue microarrays were constructed using three 2 mm cores per case. Immunohistochemical expression of LAG-3, TIM-3, VISTA, and CD8 was assessed exclusively on TILs. Survival outcomes were analyzed using Kaplan–Meier and Cox proportional hazards models. Results: LAG-3, TIM-3, and VISTA positivity rates were 26.5%, 51.5%, and 53.8%, respectively. High CD8+ TIL density was observed in 69.7% of cases. Significant positive correlations were identified among checkpoint markers (all p < 0.05); VISTA positivity did not significantly correlate with CD8 infiltration (r = 0.149, p = 0.088). LAG-3 positivity was associated with lower thyroid cartilage invasion (p = 0.006). Kaplan–Meier analysis demonstrated no significant differences in overall survival (OS) or disease-free survival (DFS) according to checkpoint expression or CD8 status. In multivariable analysis, extranodal extension (HR = 2.719, p = 0.005) and thyroid cartilage invasion (HR = 1.970, p = 0.043) were independent predictors of worse OS. CD8 negativity showed a trend toward adverse OS (HR = 1.825, p = 0.084). None of the immune markers independently predicted DFS. Conclusions: In advanced surgically treated LSCC, LAG-3, TIM-3, and VISTA expression correlate with CD8+ TIL density but do not independently predict survival outcomes. These findings suggest that alternative immune checkpoint expression reflects immune engagement rather than intrinsic tumor aggressiveness and may hold greater predictive than prognostic relevance in LSCC. Full article

Allergic asthma is associated with a reduction in the number of regulatory T cells (Tregs). Although interleukin-27 (IL-27) has been shown to modulate Tregs potentially through the Lymphocyte-activation gene 3 (Lag3) pathway, the underlying mechanism remains incompletely defined. Objective: This study sought to determine whether IL-27 ameliorates airway inflammation in asthma by modulating Tregs in a Lag3-dependent manner. Acute asthma was induced in wild-type (WT) and Lag3 knockout (Lag3^−/−) mice through sensitization and challenge with house dust mite (HDM). A treatment group received intranasal recombinant IL-27 prior to challenges. In WT mice, IL-27 administration significantly attenuated airway inflammation, goblet cell hyperplasia, and total cell counts in bronchoalveolar lavage fluid (BALF), along with reduced levels of Th2 cytokines (IL-4, IL-5). It also upregulated T-bet (Th1) mRNA expression, downregulated GATA-3 (Th2) and RORγt (Th17) levels, and increased the proportions of CD4⁺ Foxp3⁺ Tregs, CTLA4⁺ Tregs, and Lag3⁺ Tregs in lung tissue. Conversely, in Lag3^−/− mice, the protective effects of IL-27 were completely abrogated, with no observed increases in Treg populations or suppression of Th2/Th17 immune responses. The anti-asthmatic effect of exogenous IL-27 is associated with increased Treg frequency and upregulation of inhibitory markers, with Lag3 serving as a pivotal target on Tregs. Full article

Background and Objectives: Clear cell renal cell carcinoma (ccRCC) demonstrates substantial molecular and clinical heterogeneity, limiting the prognostic accuracy of conventional staging system and complicating treatment selection. CT-based radiomics and radiogenomics have emerged as promising non-invasive approaches for predicting molecular biomarkers. This review aimed to evaluate the current evidence regarding CT-based radiogenomics for the prediction of molecular markers in ccRCC, with emphasis on methodological approaches, predictive performance, and clinical applicability. Materials and Methods: A comprehensive literature search of PubMed/MEDLINE, Scopus, and Cochrane Library databases was performed for original studies published between January 2012 and December 2025. Eligible studies included patients with histopathologically confirmed ccRCC, performed CT-based radiomics feature extraction, and investigated molecular or genetic biomarkers using machine learning (ML) methods. Data regarding CT acquisition phase, segmentation strategy, radiomics features, ML algorithms, investigated biomarkers, and model performance metrics were extracted. Results and Discussion: Twenty-five retrospective studies were included. CT-based radiomics demonstrated promising performance in predicting gene mutations, including Von Hippel–Lindau (VHL), Polybromo 1 (PBRM1), BRCA1-associated protein 1 (BAP1), SET domain containing 2 (SETD2), and Lysine demethylase 5C (KDM5C), with reported area under the curve (AUC) values reaching 0.987. Radiogenomic models also showed utility in assessing hypoxia-related pathways, lipid metabolism signatures, programmed cell death profiles, immune-related markers, and tumor microenvironment characteristics, including programmed death-ligand 1 (PD-L1), Cluster of Differentiation 68 (CD68+) tumor-associated macrophages (TAMs), Cytotoxic T-Lymphocyte–Associated Protein 4 (CTLA-4), Forkhead Box P3 (FOXP3), and Ki-67 proliferation index. Predictive performance varied across biomarkers, with AUCs generally ranging from 0.68 to 0.91. Random Forest (RF), Logistic Regression (LR), Support Vector Machine (SVM), Adaptive Boosting (AdaBoost), and Gradient Boosting algorithms were most commonly applied. Conclusions: CT-based radiogenomics represents a promising non-invasive tool for molecular characterization and risk stratification in ccRCC. Standardized multicenter prospective studies, methodological homogeneity, and external validation are required before routine clinical implementation. Full article

Background/Objectives: Celiac disease (CD) is an immune-mediated enteropathy with gastrointestinal and extraintestinal manifestations. In primary care, recognition can be delayed when psychiatric symptoms, arthralgia, thyroid dysfunction, alcohol exposure, and liver-test abnormalities coexist. This case report describes a confounder-aware diagnostic approach to histologically confirmed CD in a patient with a multifactorial primary-care presentation. Methods: We report a single-patient, de-identified reflective case from routine family medicine practice, organized according to CARE case-report principles. Results: A woman in her early sixties with hypothyroidism and glaucoma presented with new low mood, anhedonia, somnolence, generalized anxiety, increased alcohol intake, poor appetite, weight loss, abdominal bloating, diarrhea, flatulence, and polyarthralgia. Initial investigations, including celiac serology obtained before gluten-free diet advice, showed mild anemia, marked hyperferritinemia, severe cholestatic and hepatocellular liver-test abnormalities, uncontrolled hypothyroidism, and strongly positive tissue transglutaminase IgA (>250 kIU/L; reference 0.0–14.9). Radiographs showed mild osteoarthritis and osteopenia without erosive arthropathy. Computed tomography excluded malignancy but showed severe diffuse hepatic steatosis and mild pancreatic atrophy. Mirtazapine was started at the index visit; after the initial laboratory results, gluten-free diet advice, alcohol-reduction counseling, and levothyroxine adjustment were undertaken. During the diagnostic episode, small-bowel biopsy demonstrated moderate-to-severe crypt hyperplastic villous atrophy with increased intraepithelial lymphocytes, and gastric biopsies showed no significant pathology; the histology was consistent with CD. Symptoms improved substantially. Longer-term objective follow-up showed persistent but improved celiac serology (tTG-IgA 49.4 kIU/L), normalization of thyroid-stimulating hormone, partial improvement in gamma-glutamyl transferase, which remained elevated, and a later iron-deficiency pattern with persistent anemia. Conclusions: This case supports targeted CD testing when anxiety or depressive symptoms occur alongside gastrointestinal symptoms, weight loss, arthralgia, hypothyroidism or documented thyroid autoimmunity, anemia, osteopenia, or liver-test abnormalities. Histology and repeat serology confirmed the diagnosis, but the psychiatric and hepatic manifestations still require cautious interpretation because hypothyroidism, alcohol exposure, steatotic liver disease, and simultaneous treatments also shaped the clinical course. Full article

Messenger RNA (mRNA) vaccines represent a transformative platform in vaccinology, with applications extending beyond SARS-CoV-2 to other infectious diseases and cancer immunotherapy. However, patients with solid tumors receiving active anticancer treatment were largely underrepresented in pivotal vaccination trials, limiting understanding of vaccine-induced immunity in this population. In this prospective exploratory study, we assessed humoral and cellular immune responses after two doses of SARS-CoV-2 mRNA vaccines in 39 patients with solid tumors undergoing active treatment. Blood samples were collected before vaccination and approximately two months after the second vaccine dose, prior to the next treatment cycle. Anti-spike IgG, neutralizing antibodies, receptor-binding domain (RBD) levels, interleukin-6 (IL-6), hematological parameters, immune cell subsets, T-cell differentiation, and early apoptosis in αβ and γδ T-cell subsets were analyzed. Vaccination induced a robust humoral response, with high post-vaccination anti-spike IgG levels (median 988.69 BAU/mL), 97.44% seropositivity, 96.88% true seroconversion among baseline IgG−/NAb− patients, and strong neutralizing antibody activity (median 85.73%). Hematological parameters and IL-6 levels remained broadly stable, suggesting no detectable increase in systemic inflammation during the study period. Cellular analyses identified a reduction in peripheral CD19+ B-cell frequencies and decreased early apoptosis, particularly in CD8+ T cells and CD3+CD56+ NKT-like cells. Although changes in T-cell frequencies and differentiation profiles were also observed, these findings were attenuated after exclusion of participants with possible prior SARS-CoV-2 exposure and should be interpreted as exploratory. Overall, these results show that patients with solid tumors receiving active treatment can mount robust humoral responses to SARS-CoV-2 mRNA vaccination and suggest measurable post-vaccination changes in lymphocyte dynamics, including reduced early T-cell apoptosis. Full article

Oral leukoplakia (OL) is a potentially malignant lesion, but only a proportion of cases undergo transformation to carcinoma (7.2% to 9.5%). The aim of this study was to analyze the possible differences and the role of immune cells in homogeneous and non-homogeneous OL at different grades of dysplasia. The infiltration density of T and B lymphocytes, macrophages, plasma cells, and cells expressing CD9 antigen was assessed semi-quantitatively in 50 OL cases using a 4-point scale—score 1 (<5%), score 2 (6–10%), score 3 (11–15%) and score 4 (16–20%)—via manual counting by two morphologists. Both clinical types of OL that showed dysplasia had noticeably higher proportions of CD138+ and CD68+ immune cells. Statistical analysis confirmed that only non-homogeneous OL with dysplasia showed an increase in the infiltration density of CD3+ and CD20+ lymphocytes. There was a statistically significant moderate positive correlation between the amount of CD9+ cells in the lamina propria and the number of labeled epithelial layers in OL of different thicknesses. Expression of CD138 and CD9 proteins in epithelial and connective tissue cells in OL indicates active epithelial–mesenchymal interaction during the premalignant stage of OL, but the expression of these markers in epithelial and immune cells was completely the opposite. The evaluation of CD3, CD20, CD9, CD138, and CD68 antigen expression, particularly in non-homogeneous leukoplakia, improves the accuracy of malignancy risk assessment in patients with dysplasia. Full article

Background: Tuber indicum is a rare edible and medicinal ectomycorrhizal fungus, and the polysaccharide fractions have attracted extensive research attention owing to their potent immunomodulatory potential. Objective/Methods: To systematically characterize the structural features and gut microbiota-mediated immunoregulatory mechanisms of water-extracted polysaccharide (TIWP) and alkali-extracted polysaccharide (TIAP) from T. indicum, two polysaccharide fractions were prepared and comprehensively structurally characterized in this study. Results: The maximum molecular weight of TIWP reached 2.65 × 10⁷ Da, which was dominated by glycosidic linkages of →3)-Glcp-(1→, →2,4)-Glcp-(1→ and →3,6)-Glcp-(1→. TIAP possessed a higher molecular weight up to 3.87 × 10⁷ Da, with predominant glycosidic bonds of →3,6)-Glcp-(1→, →4)-Glcp-(1→ and →2,4)-Glcp-(1→. In vivo bioactivity evaluation results demonstrated that both TIWP and TIAP significantly restored the proportions of CD3⁺ T and CD19⁺ B lymphocyte subsets in peripheral blood and spleen, and alleviated pathological damage in splenic and colonic tissues. Distinct regulatory patterns of gut microbiota were observed between the two polysaccharides: TIWP markedly enriched the genera Lactobacillus and Ruminiclostridium, whereas TIAP elevated the relative abundances of Lactobacillus and Alloprevotella. Untargeted metabolomics combined with KEGG pathway enrichment analysis revealed that TIWP and TIAP activated the pantothenic acid and coenzyme A biosynthesis pathway and the linoleic acid metabolism pathway. Conclusions: Collectively, TIWP and TIAP alleviated CTX-triggered immunosuppression through distinct “gut microbiota-metabolite-immunity” regulatory networks due to their structural disparities. This study provides a theoretical basis for the development of gut microecology-targeted functional foods with immunomodulatory functions. Full article

Background/Objectives: T cells within solid tumors often switch from a recirculating to a tissue-resident state, which may blunt antitumor activity, but the signal driving this switch in vivo remains unclear. We asked whether alterations in sphingosine-1-phosphate (S1P) signaling in tumor or the surrounding stromal cells are associated with T cell residency in glioblastoma (GBM). Methods: We analyzed five single-cell RNA-sequencing cohorts: three human glioma datasets, an in-house mouse CT2A glioblastoma cohort, and a human melanoma tumor-infiltrating lymphocyte cohort. T cell egress and tissue-residency programs, together with stromal S1P production and degradation, were scored per cell using curated gene modules. Cell-state contrasts were quantified as Cohen’s d, and sample-level coupling as Spearman ρ. Results: In human GBM, T cell residency programs were elevated in CD4+ helper and regulatory T cells in tumors compared with low-grade glioma controls. In mouse CT2A-derived GBM tumors, stromal S1P production correlated negatively with T cell residency across four independent stromal cell types. In human GBM microglia, S1P production was reduced compared with control microglia. The same CD8+ residency phenotype was replicated in CD3-sorted GBM tumor-infiltrating lymphocytes (TILs) and in melanoma TILs. Conclusions: A loss of stromal S1P production accompanies T cell tissue residency in GBM. Thus, stromal S1P metabolism is a candidate axis for modulating T cell recirculation and TIL biology in GBM. These findings are transcriptomic associations from single-cell RNA sequencing that do not directly measure S1P metabolite levels or signaling activity and will require functional and lipidomic validation. Full article

Arthritis is a chronic inflammatory disease characterized by progressive joint damage, in which oxidative stress and exacerbated immune responses play a critical role. Synbiotics, defined as a combination of probiotics and prebiotics, may enhance these beneficial effects; however, their efficacy depends on maintaining microbial viability throughout gastrointestinal transit. In this study, we evaluated the anti-inflammatory and antioxidant effects of Levilactobacillus brevis LBH1070. Lacticaseibacillus paracasei ATCC 334 and phenylbutazone (PBZ) were used as probiotic and allopathic drug controls, respectively. Both probiotic strains significantly reduced paw edema by 46%, comparable to PBZ (45%), and decreased lipid oxidation (33–36%) and protein oxidation (40–45%), thereby preserving the integrity of the popliteal lymph node, the lymph node closest to the edema site. Furthermore, L. paracasei ATCC 334 and L. brevis LBH1070 reduced total T helper CD4+ lymphocyte infiltration in the popliteal lymph node by 44–54% and decreased IL-1β-producing T helper lymphocytes by 77–78%, surpassing the effect of PBZ (49%). TNF-α-producing T lymphocytes were also reduced by 60–62%, compared to PBZ (53%). These findings highlight the potential of L. brevis LBH1070, its synbiotic formulation, and L. paracasei ATCC 334 as complementary treatments to modulate immune responses and oxidative stress during arthritis. Full article