Search Results (970)

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

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

Immune checkpoint inhibitors (ICIs), comprising anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), anti-programmed cell death protein 1 (PD-1), and anti-programmed death-ligand 1 (PD-L1), have transformed melanoma therapy, yet the tumour microenvironment (TME), the pivotal biological interface where therapeutic efficacy, resistance, and toxicity are determined, remains incompletely characterized. This dual systematic review and meta-analysis (PROSPERO: CRD420261374242) followed PRISMA 2020 and included 58 preclinical (B16F10/C57BL/6; 46 quantitative) and 44 clinical studies (19 quantitative) to calculate pooled standardized mean differences (SMDs) for six intratumoral TME parameters. Checkpoint blockade consistently shifted the TME toward an immune-activated state, an effect that remained robust in sensitivity analyses despite substantial heterogeneity (I-squared heterogeneity statistic (I²) = 68–88%). Preclinically, ICIs significantly increased CD8⁺ T-cell infiltration (SMD = 1.45, p < 0.001), interferon-gamma (IFN-γ) (SMD = 1.78, p < 0.001), CD8/regulatory T-cell (Treg) ratio (SMD = 0.91, p = 0.005), and apoptosis (SMD = 3.54, p < 0.001) and reduced PD-L1 (SMD = −0.88, p = 0.004) and Ki-67 (SMD = −1.43, p = 0.028). Clinically, CD8⁺ infiltration and PD-L1 both increased (SMD = 0.72, p < 0.001; SMD = 0.67, p = 0.001), contrasting with the preclinical PD-L1 decrease. Meta-regression demonstrated superior anti-PD-L1 efficacy over CTLA-4 for effector parameters: IFN-γ +3.59 (p = 0.009), CD8/Treg +10.69 (p = 0.003), apoptosis +9.76 (p = 0.004), and Ki-67 −6.28 (p = 0.040). These findings establish the TME as a critical determinant of ICI outcomes, indicate that PD-L1 amplifies effector functions in the B16F10 model, and highlight translational gaps in TME reprogramming. Full article

Background/Objective: During the last two decades, several cases presenting with circulating clonal B-cells with features consistent with possible marginal zone (MZ) derivation have been described under different terminologies. The present study aims to shed more light onto the main disease characteristics and determine prognostic factors for outcome in 98 consecutive cases with clonal B-cell lymphocytosis of marginal zone origin (CBL-MZ). Methods: This is a multicenter retrospective analysis including 98 consecutive CD5(−) CBL cases referred to our Departments between 1999 and 2017. These cases were selected based on the presence of circulating CD5(−) clonal B-cells, irrespectively of their absolute number, without B-symptoms, organomegaly, lymphadenopathy or cytopenias or any other features consistent with a known lymphoproliferative disorder. Clinical, morphologic, biochemical, immunophenotypic, histologic and molecular features of CBL-MZ cases were analyzed. Results: The median absolute lymphocyte counts (ALCs) and circulating CBLs were 6.7 × 10⁹/L and 3.447 × 10⁹/L, respectively. Paraproteinemia was found in 38%. Bone marrow (ΒΜ) was involved in all but one case. MYD-88L265P mutation was positive in 11%. Two subcategories of CBL-MZ were identified: One was characterized by lower ALC/CBL, paraproteinemia, CD38 expression, BM lymphoplasmacytic morphology and more frequent MYD-88L265P mutation. The second category displayed a leukemic picture, higher frequency of CD11c expression, hypogammaglobulinemia and elevated LDH. Treatment-free survival (TFS) was 91%, and median freedom from progression (FFP) was 95.6 months. For TFS, two factors proved significant using multivariate analysis: BM infiltration ≥ 50% and elevated LDH (RR 5.6 and 5.4, respectively). Evolution to splenic marginal zone lymphoma was a rare event (5%). A novel pattern of progression emerged, namely development of cytopenias due to extensive BM infiltration without any other disease localization. Conclusions: CBL-MZ is an indolent lymphoproliferative disorder with excellent outcome and low probability of progression. Based on our findings, CBL-MZ represents a heterogeneous entity where the vast majority of cases remain stable or develop increasing lymphocytosis. Clinically, our data also highlight that the extent of BM infiltration and elevated LDH levels appear to be the most notable predictors for introducing therapy. Full article

Epcoritamab, a subcutaneous CD3×CD20 bispecific antibody, has shown substantial activity in relapsed or refractory (R/R) B-cell lymphomas, but the immunological correlates of durable remission and treatment discontinuation remain unclear. We retrospectively analyzed 21 consecutive patients who initiated epcoritamab at our institution between 1 December 2023 and 31 December 2025, including 17 with R/R large B-cell lymphoma (LBCL) and 4 with R/R follicular lymphoma (FL). Clinical follow-up was updated through 18 May 2026. Serial cytotoxic T lymphocyte (CTL) subset and T-cell receptor (TCR) Vβ repertoire analyses were performed in selected cases. Among response-evaluable patients, the overall response rate was 9/14 in LBCL and 4/4 in FL. Median overall survival was 431 days in LBCL and 431.5 days in FL. Progression-free survival was analyzed descriptively because of the small sample size and substantial censoring. A patient with clinically and radiologically suspected central nervous system relapse of LBCL achieved radiological complete remission after epcoritamab treatment. In two LBCL and one FL case in whom epcoritamab was electively discontinued after complete remission, Vβ-skewed CTL populations were observed, and total memory CTLs exceeded total effector CTLs at discontinuation. These exploratory findings suggest that epcoritamab treatment may be associated with longitudinal remodeling of CTL subsets and Vβ-skewed CTL populations in selected responders. The potential relevance of these immunological patterns to durable response and treatment discontinuation should be validated in larger prospective cohorts with functional and sequence-based T-cell analyses. Full article

Background/Objectives: Trauma triggers complex early immune responses. However, the relationship among trauma severity, changes in immune cell survival, and circulating inflammatory mediators remains unclear. This study compared early cell viability and death patterns in CD66b⁺ granulocytes, total T lymphocytes, and CD4⁺ and CD8⁺ T-cell subsets as well as inflammatory mediator levels between patients with non-severe and severe trauma. Methods: This single-center prospective observational study included 67 adult patients with trauma who were classified into non-severe and severe trauma groups according to the Injury Severity Score (ISS < 15 vs. ISS ≥ 15). Blood samples were obtained within 1 h of arrival at the emergency department. Flow cytometry was used to assess the viability, early apoptosis, late apoptosis, and necrosis in the leukocyte subsets. Serum concentrations of intercellular adhesion molecule-1 (ICAM-1), macrophage migration inhibitory factor (MIF), CD40 ligand (CD40L), and interleukin-1 receptor antagonist (IL-1ra) were measured using enzyme-linked immunosorbent assays. Results: The severe trauma group had a significantly lower proportion of early apoptotic CD66b⁺ granulocytes than the non-severe trauma group (2.9% [1.4–6.7] vs. 6.3% [3.7–10.9], p = 0.001), whereas the live, late apoptotic, and necrotic CD66b⁺ granulocyte fractions did not differ significantly between the two groups. Most T-cell death parameters were similar between the groups, although an exploratory increase in necrotic CD4⁺ T lymphocyte abundance was observed in the severe trauma group. IL-1ra levels were significantly higher in the severe trauma group than in the non-severe trauma group and were associated with ISS in both mediator-only and adjusted sensitivity regression analyses. Conclusions: Severe trauma was associated with reduced early apoptosis in the CD66b⁺ granulocyte compartment and elevated IL-1ra levels shortly after injury compared with non-severe trauma. These findings suggest that early immune alterations after severe trauma may involve compartment-specific granulocyte death patterns and counter-regulatory inflammatory responses rather than generalized changes across leukocyte populations. Full article

Kidney transplantation remains the optimal treatment for end-stage renal disease, yet long-term allograft survival has plateaued due to persistent rejection. This review provides a comprehensive overview of the inflammatory and immune pathways implicated in kidney allograft rejection, integrating current evidence from basic and translational research. Ischemia–reperfusion injury initiates an inflammatory cascade through the release of damage-associated molecular patterns, activating Toll-like receptors and the complement system, thereby priming the alloimmune response. Innate immune cells, including macrophages, dendritic cells, and natural killer cells, bridge sterile tissue injury to adaptive alloimmunity, while the emerging concept of trained immunity reveals long-lasting epigenetic reprogramming of monocytes with direct implications for graft longevity. The adaptive response encompasses T cell-mediated rejection, driven by Th1, Th17, and CD8⁺ cytotoxic lymphocytes, and antibody-mediated rejection, mediated by donor-specific antibodies through complement activation and antibody-dependent cellular cytotoxicity. Key signalling pathways, including JAK-STAT, NF-κB, NLRP3 inflammasome, and mTOR, amplify allograft inflammation and promote progression toward chronic injury. Macrophage polarisation and macrophage-to-myofibroblast transition have been identified as major drivers of interstitial fibrosis and late graft failure. Recent advances in non-invasive biomarkers, such as donor-derived cell-free DNA and molecular phenotyping, are transforming rejection diagnostics. Emerging therapies, including costimulation blockade, anti-CD38 antibodies, complement inhibitors, and regulatory T cell-based approaches, offer the potential to shift transplant medicine toward precision-guided, tolerance-inducing strategies. This review synthesises these developments and discusses future perspectives for improving long-term allograft outcomes. Full article

Background/Objectives: Multiple sclerosis (MS) constitutes a chronic autoimmune, inflammatory, and neurodegenerative disease, with dissemination in space and time, warranting diagnosis. Epstein–Barr virus (EBV) is increasingly recognized as a key contributor to MS pathogenesis. This review summarizes evidence on EBV-related mechanisms of currently approved disease-modifying therapies (DMTs) and emerging EBV-directed therapeutic strategies in MS. Methods: A systematic search of PubMed, Embase, Cochrane, and Web of Science was performed. Original English-language studies addressing EBV-related therapeutic mechanisms or EBV-targeted interventions in MS were included; 23 studies met the inclusion criteria. Results: Current DMTs may influence EBV-related immunity through diverse mechanisms, including modulation of B-cell subsets, altered lymphocyte trafficking, reduction in EBV-specific humoral responses, and restoration of T-cell surveillance. Monoclonal antibody-based therapies, particularly anti-CD20 agents and natalizumab, appear to affect the EBV–B-cell–immune axis through distinct but complementary mechanisms. Other interventions, including interferons, glatiramer acetate, dimethyl fumarate, autologous hematopoietic stem cell transplantation, and vitamin D supplementation, may also modulate EBV-specific cellular or humoral responses, although the magnitude and durability of these effects vary. Emerging EBV-directed approaches, including EBV-specific T-cell therapy, inhibition of specific proteins, modulation of autophagy, and cholesterol-dependent viral latency, provide additional support for targeting EBV-related pathways in MS. Conclusions: The therapeutic efficacy of DMTs in MS may extend beyond nonspecific immunomodulation and involve partial disruption of EBV-driven immune persistence. Further controlled studies are required to validate EBV-related biomarkers and determine whether direct EBV-targeted therapies can provide sustained clinical benefit. Full article

Background: Colorectal cancer is a common malignancy and 5-fluorouracil (FU) remains a mainstay of chemotherapy despite its toxicity. As an important part of comprehensive tumor treatment, dual-protein (DP) nutritional intervention is attracting more and more attention. Methods: This study preliminarily evaluated the regulatory effects of DP intervention on colorectal cells of CT26 tumor-bearing mice, examining the dosage and administration methods of DP, as well as the anti-tumor effects of FU alone or in combination with DP. Results: The results showed that low- and medium-dose DP numerically increased spleen index and showed trends toward alleviating FU-induced thymic atrophy, splenic damage, nephrotoxicity, and myocardial injury. It also partly mitigated muscle wasting, prevented FU-induced shortening of the colorectal tract, and reduced intestinal injury. In addition, DP was associated with increased lymphocyte, monocyte, and platelet counts and decreased granulocytes, suggesting possible alleviation of chemotherapy-induced bone marrow suppression and a potential effect on hematopoietic function. Flow cytometry results indicated possible effects of DP on CD4⁺ T and CD8⁺ T cell proliferation or apoptosis, modulation of effector and memory phenotypes, reduced splenic neutrophil levels, balanced B cell function, and maintained natural killer cell activity. In addition, DP intervention also showed trends toward regulating hepatic lipid metabolism and partially alleviating FU-induced dyslipidemia and muscle damage. In addition, DP and FU could increase IL-2, IL-10, GM-CSF and IFN-γ and decrease IL-6 and TNF-α. Conclusions: In conclusion, a moderate dose (0.67 g/kg) of DP had the most favorable trends, and the pre-intervention mode was more effective. This study also provided exploratory data on the potential of DP in reducing chemotherapy-related toxicity. These findings will provide preliminary scientific support for nutritional therapy in colorectal cancer patients, as well as for the research, development, and application of dual-protein foods for special medical purposes. Full article

Background: The immune mechanism of diabetic kidney disease (DKD) has not yet been fully elucidated. This study aimed to characterize circulating lymphocyte subsets in patients with type 2 diabetes mellitus (T2DM), with a particular focus on DKD-related immune alterations and prognosis. Methods: Circulating T cells, B cells and NK cells were identified by flow cytometry. The primary endpoint was all-cause mortality, and overall survival was defined as the time from enrollment to death from any cause or last follow-up. Associations between lymphocyte subsets, inflammatory indices and renal function parameters were analyzed. Cox regression was used to identify factors associated with overall survival in patients with DKD and in the whole T2DM cohort. A prognostic nomogram was developed in the whole T2DM cohort to estimate 1-, 2-, 3-, and 5-year overall survival (OS) probabilities. Model performance was evaluated using the concordance index (C-index), calibration curves, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA). Mendelian randomization (MR) was performed as a further exploratory analysis to assess whether immune-related traits were genetically associated with DKD susceptibility, with inverse variance weighting (IVW) as the primary analytical method. Results: In total, 74 T2DM patients were divided into DKD (stage 3–4 of chronic kidney disease) and non-DKD groups. Median follow-up duration was 34.6 months. DKD patients exhibited elevated levels of NK cells, the monocyte-to-lymphocyte ratio (MLR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR). In patients with DKD, higher PLR and serum creatinine (SCr) were associated with poorer overall survival, whereas CD4⁺CD25⁺ T cell frequency was not significant after adjustment. In the whole T2DM cohort, higher frequency of circulating CD4⁺CD25⁺ T cells were associated with improved survival (HR 0.920, 95% CI 0.858–0.986, p = 0.019), whereas elevated PLR and SCr were linked to poorer outcomes. The exploratory nomogram incorporating CD4⁺CD25⁺ T cells, PLR, and SCr, showed acceptable internal performance in this cohort. As a separate exploratory analysis, MR suggested that genetically proxied CD4 expression on activated CD4 regulatory T cells was associated with a lower risk of DKD. Conclusions: DKD was associated with higher mortality and elevated MLR-, NLR-, PLR-, and NK cell levels in patients with T2DM. In patients with DKD, PLR and SCr were associated with overall survival, supporting the prognostic relevance of systemic inflammation and renal dysfunction. Individual lymphocyte subsets were not independently associated with survival in the DKD cohort after adjustment, whereas CD4⁺CD25⁺ T cell frequency provided additional prognostic information in the whole extended T2DM cohort analysis. Further validation is warranted. Full article

Triple-negative breast cancer is an aggressive and heterogeneous type of invasive breast cancer (BC) in which the cancer cells lack estrogen and progesterone receptors, as well as expression of the human epidermal growth factor 2 protein. This cancer tends to grow and spread faster than other BC subtypes, and is associated with a poor prognosis due to early visceral and neurological recurrences. Multidisciplinary management includes surgery, chemotherapy, radiation therapy, and immunotherapy with targeted immune checkpoint inhibitors (ICIs). The introduction of ICIs has improved outcomes in patients with TNBC, particularly in the metastatic and neoadjuvant settings. Despite these advances, a significant proportion of patients either do not respond to treatment or develop resistance to it. TNBC mortality remains high, underscoring the urgent need to identify novel prognostic and predictive biomarkers to overcome resistance to immunotherapy. Following a brief overview of the clinical features and established biomarkers of TNBC, the current review focuses on immune checkpoint proteins (ICPs) beyond PD-1 and PD-L1, and on the potential use of soluble ICPs rather than the well-established membrane-bound assays. These soluble ICPs are produced through the alternative splicing of messenger (m)RNA or the cleavage/shedding of membrane-bound proteins. This is followed by an overview of current treatment and novel predictive targets in TNBC. Additionally, the involvement of the B- and T-lymphocyte attenuator (BTLA)/herpes virus entry mediator (HVEM)/CD160 pathway and its role in the pathogenesis of BC and TNBC are reviewed, highlighting the potential use of BTLA and HVEM as biomarkers. Full article

TRAF3 (TNF Receptor Associated Factor 3) is a regulator of NF-κB signaling, acting mainly as an inhibitor of the alternative NF-κB pathway. While TRAF3 has a well-established role in immune function, mainly via B- and T-lymphocyte regulation, its roles in cancer remain unclear. Breast cancer is the most common malignancy in women and a neoplasm displaying high levels of intratumoral heterogeneity. Identifying and understanding key molecules at the interface of breast cancer cells and the immune system is crucial for advancing therapeutic strategies for breast cancer patients. Here, by employing publicly available breast cancer datasets, breast cancer cell lines stably expressing TRAF3, mass spectrometry analysis in combination with functional assays, co-culture systems, and signal pathway characterization, we sought to assess the specific role of TRAF3 in breast cancer cells and how TRAF3-expressing breast cancer cells affect their immune microenvironment. Our results indicate that TRAF3 protein overexpression inhibits colony formation through apoptosis regulation. Proteome analysis for TRAF3 interactors and over-representation analysis identified multiple protein complexes related to cell cycle, apoptosis, and immune responses. Furthermore, TRAF3-expressing breast cancer cells displayed reduced levels of PD-L1 and when co-cultured with PBMCs induced a pro-inflammatory profile with increased CD16-NK cells and higher levels of IFN-γ and TNF-α and lower IL-10 and Tregs in the culture. These findings further expand the role of TRAF3 in breast cancer, not only as a regulator of EMT and survival of cancer cells, but also as a modulator of the tumor-immune microenvironment. Full article

Background: Leukemic non-nodal variant mantle cell lymphoma (nnMCL) is an uncommon subtype of mantle cell lymphoma that lacks lymphadenopathy and generally follows an indolent clinical course. Adverse genetic alterations such as TP53 inactivation and del(13q) may have prognostic significance. Clinical findings such as splenomegaly may serve as a clue to the diagnosis and should prompt further evaluation. Case Presentation: We describe a 91-year-old woman who presented with a one-month history of anemia (hemoglobin 12.3 g/dL), mild thrombocytopenia (platelets 136 × 10⁹/L), isolated splenomegaly and no palpable lymphadenopathy. Despite a normal total white blood cell count, intermittent relative lymphocytosis with atypical lymphocytes (4%) and smudge cells was detected on the complete blood count. Peripheral blood flow cytometry demonstrated a monoclonal kappa-restricted B-cell population negative for CD5 and CD10, comprising approximately 20% of lymphocytes. Conventional karyotyping and fluorescent in situ hybridization (FISH) analysis identified del(13q), del(17p)/TP53, and IGH-CCND1 rearrangement in 8–19.5% of peripheral blood leukocytes. A month after the initial assessment, the patient presented following a fall. CT imaging of the abdomen revealed marked splenomegaly, a large subcapsular/perisplenic hematoma, and moderate-to-large hemoperitoneum. Emergent laparotomy showed an enlarged spleen (1490 g, 23 × 16 × 7.5 cm) with laceration. Histologic evaluation showed atypical lymphoid cells positive for CD20 and cyclin D1, with strong p53 expression, negative for CD5 and SOX11, and a low Ki-67 index. Similar involvement was identified in the small bowel and appendix. Targeted sequencing of splenic tissue, performed as part of a retrospective molecular characterization, identified a pathogenic TP53 variant (p.His179Gln). Conclusions: This case provides a rare opportunity to evaluate splenic and small intestinal involvement by nnMCL at both the gross and histologic levels. It highlights the importance of integrating clinical findings with flow cytometry, imaging, cytogenetic, and molecular data in establishing the diagnosis. Even when peripheral blood findings suggest a low disease burden, imaging may better define the extent of disease and support appropriate clinical assessment, particularly in elderly patients at risk for complications related to splenomegaly. Full article