Frontiers in Immunology最新文献

Introduction: Few advances have been made in the treatment of T-cell acute lymphoblastic leukemia (T-ALL). Approaches targeting histone deacetylases (HDAC) have not been thoroughly investigated in T-ALL. However, the underlying molecular mechanism of HDAC inhibition remains to be fully elucidated.

Objectives: The study aimed to evaluate the clinical outcome of chidamide (an oral selective HDAC inhibitor for HDAC1, HDAC2, HDAC3, and HDAC10) in combination with chemotherapy in relapsed or refractory T-ALL and explore the underlying molecular mechanism of HDAC inhibition in T-ALL.

Methods: The clinical outcomes of 28 patients with relapsed or refractory T-ALL, who received chidamide in combination with chemotherapy were first evaluated. Chidamide (30mg per dose) was orally administered twice a week for a total of four doses (120mg in total per patient) during the first 2 weeks of the combined salvage chemotherapy. Transcriptomic analysis was used to identify pivotal signaling pathways of histone deacetylase inhibition in T-ALL cell lines. Short hairpin RNA-mediated inhibition, co-immunoprecipitation, and a series of functional assays were performed to verify the putative signaling pathways involved in cell lines, primary patient samples, and mouse models.

Results: Of the 28 patients, 16 achieved a complete response and three achieved a partial response. As an inhibitor of histone deacetylases, chidamide significantly suppressed the proliferation of T-ALL cells and induced apoptosis and cell cycle arrest in vitro. Chidamide treatment significantly inhibited the protein level of HDAC3, but not HDAC1, HDAC2, or HDAC10, in T-ALL cell lines and primary human T-ALL cells. Moreover, the TYK2-STAT1-BCL2 signaling pathway was also substantially inhibited upon chidamide administration. Finally, overexpression of HDAC3 and TYK2 rescued the inhibitory effects of chidamide on T-ALL cells. HDAC3 was found to associate with TYK2 and contributed to activation of the TYK2-STAT1-BCL2 signaling pathway in T-ALL cells.

Conclusion: Our results highlight the effectiveness of the combination of chidamide and chemotherapy in the treatment of T-ALL patients and suggest that HDAC3 can act as a potential novel therapeutic target to inhibit the TYK2-STAT1-BCL2 signaling pathway in T-ALL.

Anaplastic Thyroid Carcinoma (ATC) represents one of the most aggressive and lethal human malignancies, characterized by rapid progression, profound therapy resistance, and a dismal prognosis. Recent advances have underscored metabolic reprogramming as a cornerstone of ATC pathogenesis, enabling tumor cells to adapt to a hostile microenvironment, sustain proliferation, and evade immune destruction. This review systematically delineates how metabolic alterations in ATC-spanning enhanced glycolysis, deregulated lipid metabolism, and aberrant amino acid utilization-orchestrate a profoundly immunosuppressive tumor immune microenvironment (TIME). We explore the mechanistic links between tumor metabolism and immune dysfunction, including nutrient competition-induced energy deficits in effector immune cells, accumulation of immunosuppressive metabolites, and metabolic regulation of immune checkpoint expression. Furthermore, we discuss the impact of metabolic crosstalk on immune cell phenotypes, fostering the recruitment and polarization of pro-tumorigenic immune populations such as M2 macrophages, regulatory T cells, and myeloid-derived suppressor cells. Clinically, we highlight the therapeutic promise of targeting key metabolic nodes and review emerging combination strategies that integrate metabolic inhibitors with immune checkpoint blockade to overcome resistance and enhance antitumor immunity. By synthesizing foundational insights with cutting-edge preclinical and clinical evidence, this review aims to provide a cohesive mechanistic framework and identify novel, metabolism-based therapeutic vulnerabilities for precision immunotherapy in ATC.

Introduction: Aberrant complement activation can cause damage to newly formed fetal-derived structures and excessive inflammatory response at the feto-maternal interface, contributing to pregnancy-related complications, including preeclampsia (PE), which is one of the most severe pathologies in new-borns. Properdin is the only known positive regulator of the complement alternative pathway, as it stabilizes the inherently labile C3bBb complex and amplifies its activity. This study describes the presence of properdin in PE and investigates its role in the pathogenesis.

Methods: We examined the distribution and expression of properdin at both the transcript and protein levels in term placental tissue, serum, placental syncytiotrophoblast microvesicles (STBMs), and circulating placental exosomes from PE women compared to healthy mothers, using RT-qPCR, western blot, immunohistochemistry, transmission electron microscopy (TEM), and immunofluorescence. To link properdin levels with alternative pathway complement factors, we also assessed the expression of C3 and C5.

Results: PE placentae showed significantly higher properdin, C3 and C5 at transcript as well as protein levels compared to healthy placentae. Conversely, properdin levels in serum, STBMs, and circulating placental exosomes were lower in PE compared to healthy pregnancies. Immunohistochemical analysis revealed properdin distribution throughout the PE placentae, with higher concentrations at the syncytial knots containing pyknotic nuclei were observed via TEM, along with elevated levels of cleaved caspase 3.

Discussion: Thus, properdin was significantly upregulated in the PE placentae, along with C3 and C5, and might be associated with the apoptotic nuclei inside syncytial knots. This evidence suggests that properdin may trigger complement-mediated damage to the placental barrier, exacerbating the development of PE placentae.

Background: Prognostic determinants in anti-glutamic acid decarboxylase (GAD) antibody-associated epilepsy remain unclear, and no validated predictive model exists. We aimed to identify prognostic factors and develop a predictive model.

Methods: This multicenter cohort included patients diagnosed with anti-GAD antibody-associated epilepsy before September 2024. Data encompassed demographics, seizure semiology, cellular and serological parameters, neuroimaging and electrophysiological findings, and treatment regimens. Favorable outcome was defined as seizure-free for ≥12 months following immunotherapy and antiseizure medications, poor outcome was defined as persistent seizures. Prognostic factors were analyzed and a predictive model was constructed.

Results: Among 91 patients, 22 (24%) achieved seizure freedom, whereas 69 (76%) continued to experience seizures despite appropriate treatment. Poor prognosis was associated with focal seizures (50% vs. 81%, p = 0.004), temporal lobe epilepsy (TLE) (23% vs. 75%, p < 0.001), musicogenic epilepsy (n = 5, all with poor seizure control), and higher seizure frequency [≥1 seizure/month (67% vs. 97%, p < 0.001)]. In contrast, a shorter disease duration from symptom onset to diagnosis [3 (IQR 0.9-26.0) vs. 8 (IQR 1.5-36.0) months, p = 0.025], a shorter interval to initiation of immunotherapy [3 (IQR 1.0-14.0) vs. 7 (IQR 1.9-27.3) months, p = 0.005], higher CD8⁺T-cell counts (829.5 ± 473.9 vs. 619.5 ± 338.6 cells/µL, p = 0.035) were associated with favorable outcomes. Multivariate logistic regression identified TLE (OR = 0.098, 95% CI: 0.028-0.341, p < 0.001) and seizure frequency (OR = 0.067, 95% CI: 0.010-0.450, p = 0.005) as independent predictors of prognosis. The prognostic model based on these two variables demonstrated good discrimination (AUC = 0.807, 95% CI: 0.696-0.919, p < 0.001) and calibration (Hosmer-Lemeshow χ² = 0.124, p = 0.740), with sensitivity of 81.8%, specificity of 72.5%, and overall accuracy of 74.7%. Internal validation with bootstrapping confirmed model stability. Risk stratification further classified patients into low- (8.7%), intermediate- (49.3-58.9%), and high-risk (93.6%) groups for poor prognosis.

Conclusion: Focal seizures, TLE, and higher seizure frequency were associated with poor prognosis, whereas early diagnosis, timely treatment, and higher peripheral CD8⁺T-cell counts were associated with favorable outcomes. TLE and seizure frequency independently predicted clinical outcomes in anti-GAD antibody-associated epilepsy. The logistic regression model effectively stratified patients, identifying those likely to achieve seizure freedom versus refractoriness.

This review provides a systematic and critical examination of the multifaceted roles of the CX3CL1/CX3CR1 axis in liver diseases. We emphasize its context-dependent duality-exhibiting both pro- and anti-inflammatory, pro- and anti-fibrotic, and pro- and anti-tumor functions across different etiologies. Moving beyond a binary good or bad" paradigm, we propose a contextual signaling model that integrates cellular source, microenvironmental cues, and intersecting pathways to explain its divergent roles. We synthesize recent advances in its involvement in NAFLD/NASH, viral hepatitis, autoimmune hepatitis, schistosomiasis, liver fibrosis and hepatocellular carcinoma. The review critically evaluates the axis's potential as a biomarker, discusses methodological advances and limitations in human studies, and analyzes therapeutic strategies with a focus on translational challenges. We conclude with a forward-looking perspective on precision medicine approaches targeting this axis.

Objective: Pegylated liposomal doxorubicin (PLD), an improved formulation of doxorubicin, offers potential advantages in targeting and reduced systemic toxicity compared to conventional anthracyclines like epirubicin. This study aimed to compare the efficacy and safety of PLD followed by paclitaxel versus epirubicin followed by paclitaxel as postoperative adjuvant therapy for triple-negative breast cancer (TNBC).

Methods: A total of 1,036 patients with TNBC who received postoperative adjuvant chemotherapy with either PLD sequential paclitaxel or epirubicin sequential paclitaxel were enrolled. The primary endpoint was disease-free survival (DFS). Adverse events were systematically documented. Multivariate Cox regression identified prognostic factors, and a predictive nomogram was developed.

Results: At median follow-up, 1-, 3-, and 5-year DFS rates were 93.39%, 84.04%, and 84.04% for the PLD group versus 93.58%, 82.38%, and 81.73% for the epirubicin group (log-rank p = 0.58). Postoperative N stage, stromal tumor-infiltrating lymphocyte (sTIL) expression, and Ki67 expression were independent predictors of DFS. The prognostic model achieved C-indices of 0.874 (training set) and 0.853 (validation set). The PLD regimen was associated with a significantly lower incidence of most adverse events; however, nausea, mucositis, and hand-foot syndrome were more frequent in the PLD group.

Conclusion: In adjuvant therapy for TNBC, PLD sequential paclitaxel demonstrated comparable efficacy to epirubicin sequential paclitaxel. However, PLD exhibited a distinct and generally more favorable safety profile, except for specific toxicities such as hand-foot syndrome and mucositis. The developed nomogram may aid in individualized prognosis prediction.

Regulatory T cells, or Tregs, are designed to limit unnecessary inflammation and serve as a safeguard mechanism to prevent tissue damage caused by heightened inflammatory responses from activated macrophages or effector T cells. Impaired Treg function has implications in autoimmunity and neuroinflammation. Neuroinflammation triggered by amyloid proteins and protein aggregates accelerates neurodegeneration due to increased cytokines and chemokines in the brains of individuals with Alzheimer's Disease and Parkinson's Disease. A simple approach involves preventing inflammation by suppressing T-effector cell activity in affected brains through boosting Tregs' function. Super-Tregs, with enhanced anti-inflammatory properties, can be engineered in vitro to combat inflammation in various tissues and, after homotropic transfer to the target tissue, prevent damage caused by inflammation. The development of Super-Tregs can be achieved through specific genetic and epigenetic modifications. Efforts to generate Super-Tregs utilizing miRNAs and miRNA-containing extracellular vesicles hold promise in treating neuroinflammation with miRNA-engineered Super-Tregs. In this review, we discuss the potential, progress, challenges, and limitations of Super-Treg development and their application in the treatment of neurodegeneration.

Background: Inflammatory bowel disease (IBD) is a chronic inflammatory disorder with increasing worldwide incidence and prevalence. While current treatment options alleviate part of the socioeconomic burden of this disease, new biomarkers and safer therapeutic approaches are needed to combat intestinal inflammation. Class-3 semaphorins (sema3A-3G) have emerged as important regulators of some biological functions underlying inflammation. For instance, SEMA3B protects against tissue damage in arthritis. However, the association of this protein with UC and its involvement in the onset of intestinal inflammation remains elusive.

Methods: To close that knowledge gap, we performed a comprehensive transcriptomic analysis of different patient cohorts. Moreover, we investigated the therapeutic efficacy of Sema3B in vivo.

Results: Our findings revealed that the expression of SEMA3B was downregulated in IBD patients compared with healthy controls. Similarly, non-responder UC patients to infliximab showed reduced transcript levels of that class-3 semaphorin before receiving the treatment. Unfortunately, the administration of recombinant Sema3B to mice subjected to DSS-acute colitis did not modify the course of the disease.

Conclusions: Therefore, SEMA3B appears to be an interesting biomarker in the context of intestinal inflammation, which deserves further validation in larger cohorts. Nonetheless, based on our in vivo results, the implication of this factor in the development of colitis seems to be minimal.

Introduction: Ionizing radiation causes severe gastrointestinal injury. B-1a cells, predominantly located in the peritoneal cavity (PerC), play a critical role in maintaining tissue homeostasis through the secretion of cytokines and natural antibodies. We aim to investigate the status of B-1a cells after irradiation, and their role in ameliorating radiation-induced intestinal injury.

Methods: C57BL/6 mice were exposed to 12-Gy partial body irradiation (PBI) and B-1a cells in the PerC, spleen and bone marrow were determined by flow cytometry. After 24 hours of PBI, 5×10⁵ B-1a cells were intraperitoneally administered in additional animals. Gut histology, intestinal barrier function, tissue injury markers, and TGF-β levels in PerC and gut tissue were assessed.

Results: Irradiation induced apoptosis in B-1a cells, resulting in depletion of B-1a cell numbers. Irradiation increased apoptotic cells in the crypts, decreased tight junction protein expression, and enhanced intestinal permeability. Adoptive transfer of B-1a cells significantly ameliorated these changes. The number of TGF-β-positive B-1a cells in PerC increased after B-1a cell transfer, accompanied by elevated TGF-β levels in both PerC and gut tissue.

Conclusion: We demonstrated that B-1a cell numbers are significantly decreased following PBI and that B-1a cell treatment alleviates radiation-induced intestinal injury possibly via the increase in TGF-β production.

Background: The pathogenesis of Guillain-Barré syndrome (GBS) may involve lymphocyte-mediated immune mechanisms. This study aimed to investigate the relationship between peripheral blood lymphocyte subsets and disease onset, severity, and the need for mechanical ventilation in patients with GBS.

Methods: This cohort study included 55 patients with GBS and 58 healthy controls. The association between peripheral blood lymphocyte subsets and the onset and severity of GBS was investigated. Among the GBS patients, 26 were classified into a non-mechanical ventilation group and 29 into a mechanical ventilation group, and the predictive value of peripheral blood lymphocyte subsets for mechanical ventilation was evaluated. Furthermore, the study examined the expression of relevant lymphocyte subsets in the sciatic nerve of experimental autoimmune neuritis (EAN) rat models at different disease stages.

Results: ROC curve analysis showed that both CD8⁺ T cell counts and NK cell counts had moderate discriminative ability in distinguishing patients with GBS from controls. The AUC for CD8⁺ T cell counts was 0.73 (95% CI: 0.637-0.836), with an optimal cutoff value of 394.39 cells/μL, while the AUC for NK cell counts was 0.81 (95% CI: 0.731-0.893), with an optimal cutoff value of 147.7 cells/μL. Total lymphocyte counts, total T cell counts, CD8⁺ T cell counts, and CD4⁺ T cell counts were negatively correlated with Hughes peak score (all P ≤ 0.005). Logistic regression showed that higher peripheral CD4⁺ T cell counts was associated with reduced need for mechanical ventilation (OR = 0.997; 95% CI: 0.994-1.000, P = 0.032). The combined ROC analysis of CD8⁺ T cell counts, CD4⁺ T cell counts, and the EGRIS score demonstrated good discriminative ability for identifying GBS patients who required mechanical ventilation, with an AUC of 0.87 (95% CI, 0.772-0.971, P < 0.001). In the EAN model, CD4⁺ T cell expression was increased in sciatic nerve tissue.

Conclusion: Peripheral blood lymphocyte subsets show potential value in differentiating disease severity and the need for mechanical ventilation in patients with GBS, highlighting the clinical significance of immune cell profiling in risk stratification.