Frontiers in Immunology最新文献

{"title":"Invariant Natural Killer T lymphocytes as natural sensors for microbes: a two-edged sword in liver diseases.","authors":"Michelangelo Bauwelz Gonzatti, Alexandre Castro Keller","doi":"10.3389/fimmu.2025.1662906","DOIUrl":"10.3389/fimmu.2025.1662906","url":null,"abstract":"<p><p>The liver is a complex immunological organ characterized by a dual blood supply from the hepatic artery and portal vein, which continuously exposes it to microbial and dietary antigens, as well as potential pathogens that gain access to the circulation. This characteristic renders the liver particularly susceptible to immune activation, which may disrupt hepatic homeostasis and promote inflammation, thereby contributing to the pathogenesis of various liver diseases. Invariant natural killer T (iNKT) cells, a subset of liver-resident T lymphocytes, act at the intersection of hepatic immune surveillance and inflammatory responses. These cells are capable of rapid activation in response to glycolipid antigens presented by CD1d molecules and a broad range of pro-inflammatory stimuli, including cytokines and damage-associated molecular patterns. Perturbations in the intestinal barrier or dysbiosis of the gut microbiota can exacerbate hepatic exposure to microbes and metabolites, amplifying inflammatory signaling within the liver microenvironment. Although mouse models do not fully capture the complexity and heterogeneity of human liver diseases, the conserved nature of iNKT cell responses across species makes them useful for study their potential roles in human pathology. Furthermore, the discovery of specific iNKT agonists with polarizing ability emerges as an alternative to modulate the inflammatory microenvironment and the progression of hepatic damage. Therefore, a comprehensive understanding of iNKT cell dynamics under both physiological and pathological conditions is essential for the development of targeted therapeutic strategies to prevent or mitigate inflammatory liver diseases.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1662906"},"PeriodicalIF":5.9,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12535845/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145344768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Case Report: Novel <i>IL10RB</i> variant causing very early onset-inflammatory bowel disease.","authors":"Yusuf Usman, Christopher P Ptak, Valeria C Cohran, Brian E Nolan, Aisha Ahmed, Aaruni Khanolkar","doi":"10.3389/fimmu.2025.1655475","DOIUrl":"10.3389/fimmu.2025.1655475","url":null,"abstract":"<p><strong>Background: </strong>Very early onset-inflammatory bowel disease (VEO-IBD) can arise from monogenic defects affecting immune regulation. We report a male child with VEO-IBD caused by a homozygous, loss-of-function <i>IL10RB</i> variant (c.562T>G; p.C188G) that has not been previously reported for this disorder.</p><p><strong>Case presentation: </strong>A male infant of Hispanic descent was admitted to our hospital at the age of 8 months due to intractable colitis, perianal fistulas and growth faltering. Endoscopy at nine months of life revealed pancolitis and gastritis. Despite multiple courses of steroids and use of sulfasalazine, their disease remained active. Standard biologic therapies (infliximab and adalimumab) were trialed in the second year of life without improvement. Given the very early onset and severe phenotype, functional testing by phosflow to evaluate the IL-10 signaling pathway demonstrated the absence of STAT3 phosphorylation in response to IL-10 and follow up genetic testing identified a novel homozygous <i>IL10RB</i> missense variant (c.562T>G; p.C188G). Subsequent protein structure analysis using AlphaFold corroborated this loss-of-function phenotype. The patient's condition was partially controlled with anakinra (IL-1 receptor antagonist) as a bridge therapy. At the age of 3 years, the patient underwent an allogeneic hematopoietic stem cell transplant (HSCT) from an unrelated umbilical cord blood donor; however, they experienced engraftment failure, likely due to persistent hyperinflammation and the choice of cord blood for HSCT. The patient continues to have active disease requiring on-going medical management and supportive care.</p><p><strong>Conclusion: </strong>We report a novel, loss-of-function <i>IL10RB</i> variant causing VEO-IBD, thus expanding the genotypic spectrum of this condition. This case highlights the diagnostic and therapeutic challenges of IL-10R deficiency-related VEO-IBD. It also underscores the importance of early recognition of monogenic causes of IBD, use of interim immunomodulatory therapies, and the need for optimal timing and donor selection for HSCT.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1655475"},"PeriodicalIF":5.9,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12536031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145344884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential perception of virulence factors of uropathogenic <i>Escherichia coli</i> at the level of chromatin dynamics of infected host cells.","authors":"Krishnendu Mukherjee, Wiebke Aschenbach, Annika Hilger, Judith Saur, Ulrich Dobrindt","doi":"10.3389/fimmu.2025.1642683","DOIUrl":"10.3389/fimmu.2025.1642683","url":null,"abstract":"<p><strong>Introduction: </strong>Uropathogenic <i>Escherichia coli</i> (UPEC) evades the innate immune response in the urinary tract through the coordinated action of various virulence factors encoded within distinct pathogenicity islands (PAIs). We have demonstrated that UPEC infection leads to the epigenetic regulation of host gene expression; however, the specific role of PAI-encoded virulence factors in this process remains largely unexplored.</p><p><strong>Methods: </strong>In this follow-up study, we infected <i>Galleria mellonella</i> larvae with individual PAI deletion mutants of UPEC strain 536 to investigate the relationship between UPEC virulence determinants and host epigenetic regulation.</p><p><strong>Results: </strong>The loss of different pathogenicity islands (PAI I₅₃₆ to PAI VI₅₃₆) led to varying degrees of virulence attenuation in larvae and an increased sensitivity to <i>G. mellonella</i> hemolymph compared to the wild-type UPEC strain 536. Notably, infection with the different PAI mutants resulted in distinct histone modification patterns, including hypo- or hyper-acetylation of specific histone H3K9 and H4K5 residues. In addition, the loss of selected PAIs led to altered expression of histone acetyltransferases and histone deacetylases as well as changes in the expression of antimicrobial innate immune genes. We show that UPEC-induced histone acetylation changes in larvae were conserved in human bladder epithelial cells, underscoring the translational relevance of the <i>G. mellonella</i> system.</p><p><strong>Discussion: </strong>These findings reveal that specific PAI-encoded virulence factors trigger epigenetic and immunological changes in <i>G. mellonella</i> which may help us to also better understand relevant processes in the course of infection in humans.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1642683"},"PeriodicalIF":5.9,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12535880/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145344683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Current landscape of T-cell engagers in early-phase clinical development in solid cancers.","authors":"Andrea Spinazzola, Giovanni Maria Iannantuono, James L Gulley, Elena Giudice, Marco Filetti, Stefano Sganga, Francesca Lo Bianco, Charalampos S Floudas, Gennaro Daniele","doi":"10.3389/fimmu.2025.1665838","DOIUrl":"10.3389/fimmu.2025.1665838","url":null,"abstract":"<p><p>T-cell engagers (TCEs) are an emerging class of immunotherapeutic agents designed to harness the immune system to target and eliminate cancer cells. These molecules bridge T lymphocytes with tumor cells, generating an immunologic synapse that leads to potent immune-mediated tumor destruction. Although the clinical activity of TCEs in patients with solid tumors remains insufficient, recent technological advancements have led to the development of several candidates in early-phase clinical trials, with some showing encouraging signs of efficacy. This review examines the current landscape of TCEs in early clinical development for the treatment of solid tumors, describing their mechanism, clinical progress, efficacy, and challenges.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1665838"},"PeriodicalIF":5.9,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12536262/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145344670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A high eosinophil proportion increases the risk of skin-related adverse events induced by apalutamide in patients with prostate cancer.","authors":"Yoshihiko Tasaki, Taku Naiki, Yoshihisa Mimura, Yosuke Sugiyama, Misato Tomita, Toshiharu Morikawa, Takashi Nagai, Rei Unno, Toshiki Etani, Shuzo Hamamoto, Yukihiro Umemoto, Takahiro Yasui, Yoko Furukawa-Hibi","doi":"10.3389/fimmu.2025.1681734","DOIUrl":"10.3389/fimmu.2025.1681734","url":null,"abstract":"<p><strong>Background: </strong>Skin-related adverse events (AEs) induced by apalutamide occur frequently in Japanese patients with prostate cancer. However, biomarkers for predicting these skin-related AEs have not yet been identified. Therefore, this study investigated whether the proportion of eosinophils could serve as a predictive biomarker for skin-related AEs in Japanese patients with prostate cancer treated with apalutamide.</p><p><strong>Methods: </strong>A total of 109 patients were enrolled in this study. Among them, 79 patients with prostate cancer who received apalutamide were categorized into two groups: the skin AE group (n = 45) and the non-skin AE group (n = 34), based on whether they experienced skin-related AEs of any grade. The eosinophil proportions in baseline samples collected before treatment were then analyzed.</p><p><strong>Results: </strong>The baseline eosinophil proportion was significantly higher in the skin AE group compared with the non-skin AE group (<i>P</i> < 0.05). The optimal cut-off value of the eosinophil proportion for predicting skin-related AEs of any grade was 1.8% (area under the receiver operating characteristic curve [AUC] = 0.768). In multivariate analysis, an eosinophil proportion ≥1.8% was identified as an independent factor associated with skin-related AEs of any grade (odds ratio, 13.3; 95% confidence interval, 3.82-46.4; <i>P</i> < 0.05).</p><p><strong>Conclusion: </strong>The baseline eosinophil proportion may serve as a predictive biomarker for skin-related AEs of any grade in Japanese patients with prostate cancer treated with apalutamide.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1681734"},"PeriodicalIF":5.9,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12536007/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145344851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Administration of statins is correlated with favourable prognosis in lung cancer patients receiving immune checkpoint inhibitors.","authors":"Jingjing Yang, Jie Lin, Huaijuan Guo, Wenjuan Wu, Jiaxin Wang, Jingxian Mao, Wenbin Fan, Yang Lu, Ying Wang, Xuebing Yan","doi":"10.3389/fimmu.2025.1638677","DOIUrl":"10.3389/fimmu.2025.1638677","url":null,"abstract":"<p><strong>Objective: </strong>Statins are commonly used for cardiovascular diseases and recent studies have supported their anti-cancer role in numerous human malignancies. This study aims to investigate their prognostic impact in lung cancer patients receiving immune checkpoint inhibitors (ICIs).</p><p><strong>Methods: </strong>A retrospective analysis was performed based on the clinical data from 235 lung cancer patients who received ICI therapy between 2019 and 2024 in three hospitals. The correlation of statin use with overall survival (OS) or progression-free survival (PFS) was analyzed. Then, a comprehensive bioinformatics analysis was used to identify prognostic target genes of statins and investigate their correlation with immune infiltration, followed by validation in an independent cohort and cellular experiments.</p><p><strong>Results: </strong>In the whole cohort, 80 patients (34.0%) received statins. The statin users had a significantly better OS and PFS than the non-statin users. Statin use was an independent favorable prognostic factor for ICI-treated lung cancer patients. Transcription factor RAR-related orphan receptor alpha (RORA) was identified as a favorable prognostic target gene of statins. RORA was found to be downregulated in lung cancer tissues and correlated with infiltration of some immune cells. In the validation cohort, RORA expression was positively correlated with CD8⁺ T cell infiltration in lung cancer tissues, and improved prognosis in lung cancer patients receiving ICIs. Atorvastatin treatment increased RORA expression and RORA knockdown partly antagonized the inhibitory role of Atorvastatin on the malignant characteristics of lung cancer cells <i>in vitro</i>.</p><p><strong>Conclusion: </strong>Statin use was significantly correlated with improved prognosis in lung cancer patients receiving ICIs. Statins may enhance ICI efficacy partly through RORA. Due to study limitations, the actual role of statins and their target genes in anti-cancer immunity needs further investigations.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1638677"},"PeriodicalIF":5.9,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12535986/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145344927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognostic value of neutrophil to lymphocyte ratio in patients with esophagus cancer receiving neoadjuvant therapy: a systematic review and meta-analysis.","authors":"Longwei Ma, Jiaxing He, Ping Li, Long Ma, He Wang, Yanchao Deng","doi":"10.3389/fimmu.2025.1615962","DOIUrl":"10.3389/fimmu.2025.1615962","url":null,"abstract":"<p><strong>Background: </strong>Growing research reveals a relation of the neutrophil-to-lymphocyte ratio (NLR) to clinical outcomes of the esophageal cancer (EC) population undergoing neoadjuvant therapy. However, current findings remain inconclusive and somewhat controversial.</p><p><strong>Methods: </strong>PubMed, Embase, Web of Science, and the Cochrane Library were thoroughly retrieved until April 22, 2025 to collect studies on the link of NLR to prognosis among the EC population following neoadjuvant therapy. Eligible studies were selected as per predefined eligibility criteria. The primary outcomes encompassed overall survival (OS), recurrence-free survival (RFS), and pathological complete response (pCR). Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were pooled for prognostic significance assessment along with subgroup analyses. The evidence was graded via the GRADE method.</p><p><strong>Results: </strong>11 cohort studies involving 2,220 patients were included in the analysis. The results demonstrated a notable link of risen NLR to less favorable OS (HR = 1.99, 95% CI: 1.43-2.76, P < 0.0001; I² = 88%), shorter RFS (HR = 2.69, 95% CI: 1.77-4.08, P < 0.00001; I² = 47%), and lower pCR rates (OR = 0.67, 95% CI: 0.47-0.94, P = 0.02; I² = 62%). Subgroup analyses by sample size, follow-up length, age, treatment modality, and NLR cut-off value consistently demonstrated a strong correlation between elevated NLR and shortened RFS across all subgroups. Notably, in patients receiving neoadjuvant chemoradiotherapy (NCRT), the link of increased NLR to OS and RFS appeared more robust compared to those receiving neoadjuvant chemotherapy (NCT) alone.</p><p><strong>Conclusion: </strong>In patients with EC undergoing neoadjuvant therapy, a higher pre-treatment NLR is significantly linked to worse OS and RFS, as well as a lower likelihood of achieving pCR. Therefore, NLR can be a valuable prognostic biomarker in this patient population, potentially aiding clinicians in risk stratification and treatment decision-making.</p><p><strong>Systematic review registration: </strong>https://www.crd.york.ac.uk/prospero/, identifier CRD42024610088.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1615962"},"PeriodicalIF":5.9,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12535995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145344930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Featured intestinal microbiota associated with hepatocellular carcinoma in various liver disease states.","authors":"Xiu Sun, Zhewen Zhou, Xin Chi, Danying Cheng, Yuanyuan Zhang, Yifan Xu, Yanxu Hao, Ying Duan, Wei Li, Yingying Zhao, Shunai Liu, Ming Han, Xi Wang, Song Yang, Calvin Q Pan, Huichun Xing","doi":"10.3389/fimmu.2025.1674838","DOIUrl":"10.3389/fimmu.2025.1674838","url":null,"abstract":"<p><strong>Objective: </strong>This study aimed to identify distinct intestinal microbiota associated with hepatocellular carcinoma (HCC) and to construct a predictive model for HCC.</p><p><strong>Methods: </strong>A case-control study was conducted including patients with chronic hepatitis B (CHB), liver cirrhosis (LC), HCC, and healthy controls (HC). Fecal 16S rDNA sequences were analyzed using bioinformatics approaches. Specific intestinal microbiota were identified through stratified analysis, and a predictive model was subsequently constructed.</p><p><strong>Results: </strong>A total of 152 subjects were enrolled, including CHB (n = 33), LC (n = 59; 25 compensated cirrhosis, CC; 34 decompensated cirrhosis, DC), HCC (n = 30; 5 CHB-HCC, 9 CC-HCC, and 16 DC-HCC), and HC (n = 30). A significant overall difference in alpha diversity was observed across the groups (Chao1: P = 0.010,ϵ²= 0.056; ACE: P = 0.016,ϵ²= 0.049). In the CHB-HCC, CC-HCC, and DC-HCC groups, the abundance of <i>Bacteroides</i>, <i>Prevotella</i>, and <i>Faecalibacterium</i> gradually decreased, whereas <i>Klebsiella</i>, <i>Haemophilus</i>, and <i>Streptococcus</i> increased. Comparison of CHB vs. CHB-HCC, CC vs. CC-HCC, and DC vs. DC-HCC revealed consistent microbial shifts across disease stages. In particular, <i>Roseburia</i>, <i>Veillonella</i>, <i>Megasphaera</i>, and <i>Paraprevotella</i> were increased irrespective of liver disease stage. By combining microbiota profiles with clinical indicators, we developed a predictive nomogram that achieved an AUC of 0.865 in the training cohort and 0.848 in the external validation cohort.</p><p><strong>Conclusion: </strong>Intestinal microbiota were associated not only with liver disease stage but also with the occurrence of HCC itself. Characteristic microbiota may serve as effective biomarkers for predicting HCC.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1674838"},"PeriodicalIF":5.9,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12536024/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145344653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effective MRD clearance and long-term survival with CD19 CAR-T in pediatric B-ALL patients with MRD positivity or chemotherapy intolerance.","authors":"Yu Wang, Yue-Ping Jia, Ai-Dong Lu, Le-Ping Zhang, Yu-Juan Xue, Hui-Min Zeng","doi":"10.3389/fimmu.2025.1672509","DOIUrl":"10.3389/fimmu.2025.1672509","url":null,"abstract":"<p><strong>Background: </strong>While CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy demonstrates remarkable efficacy in relapsed/refractory (R/R) ALL, its application in earlier treatment lines requires further investigation. This study aimed to evaluate the efficacy, safety, and cellular kinetics of CD19 CAR-T therapy in pediatric B-cell ALL (B-ALL) patients with minimal residual disease (MRD) positivity or chemotherapy intolerance.</p><p><strong>Methods: </strong>Between 2017 and 2021, 50 eligible pediatric B-ALL patients (with positive MRD or chemotherapy intolerance) received CD19 CAR-T therapy. Efficacy endpoints included complete remission (CR), MRD-negative CR (MRD-CR), overall survival (OS), and leukemia-free survival (LFS). CAR-T cellular kinetics parameters (C_max, AUC_0-28d, persistence) were quantified via qPCR and correlated with clinical outcomes. Safety assessment covered cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and infections.</p><p><strong>Results: </strong>At day 28 post-infusion, the CR and MRD-CR rates were 98% and 96%, respectively. With a median follow-up of 68.7 months, the 5-year OS and LFS rates were 74.9% and 67.8%. Multivariate analysis identified prolonged B-cell aplasia (BCA) duration (HR = 0.969, <i>p</i> = 0.021) and female sex (HR = 0.235, <i>p</i> = 0.032) as independent protective factors for LFS. Cellular kinetics analysis showed effective <i>in vivo</i> expansion in 98% of patients, with a median C_max of 30,860 copies/μg DNA and a median time-to-peak of 10.5 days. The MRD-CR group at day 28 exhibited significantly higher C_max and AUC_0-28d (<i>p</i> = 0.017; <i>p</i> = 0.029) and superior CAR-T persistence (<i>p</i> = 0.030) compared to the non-MRD-CR group. Pre-infusion tumor burden levels did not significantly impact CAR-T expansion or duration. BCA duration positively correlated with CAR-T persistence (r=0.570, <i>p</i> < 0.001), but CAR-T expansion parameters (Cmax and AUC0-28d) did not significantly influence BCA. Regarding safety, grade ≥3 CRS occurred in 16% of patients, and ICANS in 10%. Pre-infusion MRD ≥ 10^-3 was an independent predictor of severe CRS.</p><p><strong>Conclusion: </strong>CD19 CAR-T therapy demonstrates highly effective MRD clearance and provides long-term survival benefits with a manageable safety profile in pediatric B-ALL patients with MRD positivity or chemotherapy intolerance. Effective CAR-T expansion occurs even at low tumor burdens. These findings support the potential for advancing CAR-T therapy into earlier treatment lines, although its value requires further validation in prospective studies.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1672509"},"PeriodicalIF":5.9,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12536014/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145344709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroinflammation: targeting microglia for neuroprotection and repair after spinal cord injury.","authors":"Roberta Ramos Cavalcanti, Fernanda Martins Almeida, Ana Maria Blanco Martinez, Camila Marques Freria","doi":"10.3389/fimmu.2025.1670650","DOIUrl":"10.3389/fimmu.2025.1670650","url":null,"abstract":"<p><p>Neuroinflammation is a tightly regulated process essential for central nervous system (CNS) homeostasis, debris clearance, and defense against pathogens. Microglia, the resident immune cells of the CNS, are central to this response, supporting plasticity and repair under normal conditions. Following spinal cord injury (SCI), however, this response becomes amplified and dysregulated. Early microglial activation can be protective, but prolonged activation drives the release of pro-inflammatory and cytotoxic mediators that exacerbate secondary injury and hinder repair. Microglia also engage in complex crosstalk with astrocytes, oligodendrocytes, neurons, and infiltrating immune cells, orchestrating both protective and damaging processes. This dual and dynamic nature underscores their importance as both targets and modulators in SCI therapies. This review aims to examine the roles of microglia in SCI, summarizes SCI pathology, the specific roles of microglia and macrophages, and outlines translational efforts to modulate their activation, while also highlighting the barriers to clinical application. Evidence from preclinical studies and emerging therapeutic strategies, including pharmacological, cell-based, and exosome-based interventions, demonstrates the potential to reduce harmful inflammation, promote neuroprotection, and support functional recovery. Despite these advances, clinical translation remains limited, constrained by the heterogeneity of microglial responses, narrow therapeutic windows, and patient-specific variability. These challenges often lead to modest or inconsistent clinical outcomes. Future strategies will require precision, multi-targeted approaches that integrate microglial modulation with the preservation of the blood-brain barrier (BBB) and the regulation of peripheral immune infiltration. Harnessing the regenerative potential of microglia, guided by biomarker-based patient stratification and a deeper understanding of their dynamic roles, offers the most promising path toward meaningful recovery after SCI.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1670650"},"PeriodicalIF":5.9,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12535890/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145344790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}