Immunology最新文献

Chimeric antigen receptor T (CAR-T) cell therapy has revolutionised the treatment of hematologic malignancies, achieving durable and robust responses. However, the application of CAR-T cells in solid tumours remains limited by a complex network of barriers, most notably poor tumour infiltration. The key obstacles include mismatch between chemokines and receptors, abnormal tumour vasculature, immunosuppressive cellular populations (such as myeloid-derived suppressor cells, tumour-associated macrophages and regulatory T cells), dense network of cancer-associated fibroblasts and extracellular matrix, T cell dysfunction and exhaustion, metabolic limitations within the tumour microenvironment, tumour heterogeneity and transport limitations related to tumour location. By integrating mechanistic insights with innovative bioengineering and combination approaches, this review systematically elaborates on the factors that limit the infiltration of CAR-T cells and emphasises transformation strategies for improving the efficacy, durability and invasiveness of treating solid tumours.

Intensive care unit (ICU) patients with coronavirus disease 2019 (COVID-19) have an increased risk of bacterial coinfections, including ventilator-associated pneumonia (VAP), bloodstream infections (BSI) and catheter-associated urinary tract infections (CA-UTI). The objective was to investigate the prevalence, risk factors and spectrum of bacterial coinfections in patients with COVID-19 admitted to the ICU. It is a single-centre retrospective cohort study. Data from 201 patients with COVID-19 admitted to the University Clinical Intensive Care Hospital in Bialystok, Poland, between March 2020 and July 2021 were analysed. The prevalence of coinfections, risk factors and causative agents were assessed. Objective comparisons of data were performed by evaluating related studies and reviews. Bacterial coinfections developed in 70% of the 201 patients studied. The most frequent types were VAP, occurring in 47.5% of patients with bacterial coinfections, BSI and CA-UTI. Prolonged ventilatory support (mean duration of 13.3 days in the bacterial coinfection group) and prolonged ICU stay (mean of 15.3 days) were associated with an increased risk of these infections. The predominant pathogens were Klebsiella pneumoniae and Staphylococcus aureus, with Klebsiella pneumoniae extended spectrum beta-lactamases (ESBL) being the most frequently isolated pathogen after 48 h of ICU admission, detected in 121 instances. Bacterial coinfections are common in COVID-19 patients in the ICU and are associated with specific risk factors and pathogens. Vigilant monitoring, antimicrobial stewardship and infection prevention measures are needed to improve patient outcomes.

This study aimed to characterise the expression and functional heterogeneity of CD49f across CD4+ T cell subsets in human peripheral blood, and to investigate alterations in regulatory T cells (Tregs) and CD4+ T cells in patients with systemic lupus erythematosus (SLE), together with their clinical relevance. A total of 43 newly diagnosed, treatment-naïve SLE patients and 21 age- and sex-matched healthy controls were enrolled. Peripheral blood mononuclear cells were analysed by flow cytometry to assess CD49f expression in CD4 + FoxP3+ Tregs and non-Treg CD4+ T cells. Phenotypic and function-related markers were compared between CD49f + and CD49f- subsets. IL-10 production was evaluated as a functional readout in CD49f-defined Treg subsets. Associations between CD49f-related populations and clinical parameters were analysed, and receiver operating characteristic (ROC) curve analysis was performed to explore their potential clinical relevance. CD49f expression was higher in CD4 + FoxP3+ Tregs than in other CD4+ T cells. CD49f + CD4+ T cells exhibited increased CD226 and decreased CD45RA expression, consistent with an activated phenotype. CD49f + Tregs were enriched in the CD45RA-FoxP3int subset and showed higher CD226 but lower GZMB and Helios expression, indicating attenuated suppressive phenotypic features. In healthy controls, CD49f + Tregs displayed significantly higher IL-10 production than CD49f- Tregs, whereas this functional distinction was lost in SLE patients. The proportions of CD49f + subsets were significantly increased in SLE and correlated with multiple clinical indicators. ROC analysis revealed moderate discriminative performance of CD49f-related subsets, with AUC values ranging from 0.640 to 0.786. In conclusion, CD49f identifies distinct phenotypic and functional states within CD4+ T cells and Tregs. CD49f + CD4+ T cells exhibit activation features, while CD49f + Tregs show phenotypic attenuation accompanied by functional heterogeneity that is preserved in health but disrupted in SLE. Increased CD49f expression in SLE reflects immune imbalance and suggests potential value as a cellular immunological marker rather than a standalone diagnostic tool.

Over the past several decades, cure rates for paediatric hematologic malignancies have improved due to advances in cancer therapy. However, numerous obstacles limit the therapeutic efficacy of paediatric solid tumours, including the tumour's immunosuppressive microenvironment and the lack of specific tumour antigens for targeted therapy. Cancer vaccines, a form of immunotherapy, have been under development for more than half a century. Advances in immunology, materials science, sequencing technologies and bioinformatics have revolutionised cancer vaccine development, achieving substantial success in the prevention and treatment of solid tumours. Despite these achievements, the application of cancer vaccines developed for adults is not fully transferable to paediatric solid tumours because of differences in immune status and metabolic capacity. In clinical practice, most solid tumour vaccines designed for adults are applied directly to paediatric patients without modifications tailored to the unique features of the paediatric immune system. Limited attention has been given to designing cancer vaccines with improved efficacy and reduced toxicity for children and infants. This review discusses paediatric solid tumour vaccines from the immune system against tumour to different antigen types of cancer vaccines, illustrating the unique cancer-immunity cycle of young people and some potential strategies for vaccine modification. Additionally, it discusses the application of paediatric solid tumour vaccines through clinical trial data for conditions such as neuroblastoma, brain tumours and sarcomas. Challenges and potential solutions for enhancing vaccine efficacy, minimising side effects and broadening clinical applications are also addressed.

Glioblastoma (GBM) is the most aggressive primary brain tumour in adults, characterised by rapid progression, extensive heterogeneity, and poor outcomes despite surgery, radiotherapy, and temozolomide (TMZ). A subpopulation of glioblastoma stem cells (GSCs) with self-renewal and multi-lineage differentiation capabilities drives tumour initiation, progression, recurrence, and therapeutic resistance. GSCs evade conventional treatments via enhanced DNA repair, multidrug efflux, activation of survival pathways, epigenetic reprogramming, and entry into quiescent states. Moreover, these cells utilise key immune escape mechanisms, such as downregulation of major histocompatibility complex molecules and the secretion of immunosuppressive factors, to escape detection and destruction by the immune system. Evidence suggests that transformed neural stem cells are a likely source of GSCs, with key survival networks including EGFR, FGFR, HGFR, and PI3K/AKT/mTOR signalling. Their phenotypic plasticity and adaptability to the tumour microenvironment further complicate eradication. Stem cell-based strategies utilising NSCs, MSCs, haematopoietic stem/progenitor cells, or induced pluripotent stem cells can effectively deliver immunomodulators to counteract these immune evasion mechanisms, exploiting tumour tropic migration to deliver therapeutic payloads into hypoxic and infiltrative niches. Approaches such as suicide gene therapy, oncolytic virus delivery, and CXCL12-CXCR4 axis modulation aim to target both proliferative and dormant GSCs. Preclinical studies demonstrate promising efficacy, yet challenges remain, including safety concerns, variability in outcomes, and the limited translational relevance of current models. This review provides a concise overview of GSC biology, resistance mechanisms, and emerging stem cell-based interventions, highlighting opportunities and obstacles in developing effective therapies for GBM.

Natural killer (NK) cell immunosuppression represents a critical factor in patients with progressive hepatocellular carcinoma (HCC), yet its underlying characteristics at the single-cell level remain poorly defined. This study investigates the functional and metabolic alterations in NK cells associated with progressive HCC. We performed single-cell RNA sequencing (scRNA-seq) on peripheral blood samples from six treatment-naïve HCC patients, categorised into progressive and stable disease groups based on a 3-year follow-up. This was complemented by multicolor flow cytometry of peripheral blood, alongside multicolor fluorescence analyses of paired tumour and adjacent tissues. Our analyses revealed a significant reduction in NK cell proportion and a marked downregulation of immune-related genes in patients with progressive HCC. scRNA-seq further identified a distinct NK cell characterised by high expression of HAVCR2 (TIM3). Compared to TIM3^-NK cells, TIM3⁺NK cells exhibited an exhausted phenotype, evidenced by upregulated CD39 and TIGIT, impaired functional capacity (reduced CD107a and IFN-γ) and downregulated key glycolytic enzymes (HK2, ATP5a). Clinically, high TIM3 expression correlated with shorter progression-free survival and an increased risk of tumour progression. Collectively, our findings delineate a state of NK cell immunosuppression and metabolic impairment in progressive HCC, potentially driven by glycolytic reprogramming and establish TIM3 as a critical marker and potential therapeutic target.

This review provides an in-depth analysis of the complex bidirectional interaction mechanisms between tumour-associated macrophages (TAMs) and T cells in the tumour microenvironment (TME). It elaborates on how TAMs, especially M2-type TAMs, suppress the anti-tumour function of T cells and induce their exhaustion through multiple pathways, such as secreting immunosuppressive cytokines (e.g., IL-10, TGF-β), highly expressing immune checkpoint ligands (e.g., PD-L1), recruiting other immunosuppressive cells (e.g., Treg cells), depleting key metabolites (e.g., arginine), and remodelling the extracellular matrix (ECM), thereby promoting tumour immune escape and disease progression. Meanwhile, the review also explores how T cells reverse-regulate the polarization state of TAMs through the activation of the CD40-CD40L axis and the secretion of specific cytokines (e.g., IFN-γ or IL-4). Based on this, the review systematically proposes innovative immunotherapy strategies targeting this key bidirectional interaction, including blocking the recruitment of TAMs (e.g., CCL2/CCR2, CXCL12/CXCR4 inhibitors), directly eliminating TAMs (e.g., CSF1R inhibitors, bisphosphonates, trabectedin), or reprogramming them into anti-tumour M1-type (e.g., CD40 agonists, TLR agonists, CD47-SIRPα axis blockers), and emphasises the great potential of combining these TAM-targeting strategies with immune checkpoint inhibitors (e.g., anti-PD-1/PD-L1 antibodies). These combined therapies aim to synergistically enhance efficacy and overcome the current challenges of drug resistance in immunotherapy, offering new hope for more durable and effective treatment for cancer patients. Additionally, the review looks forward to the application prospects of advanced cell therapies such as nanoparticle delivery systems and chimeric antigen receptor macrophages (CAR-M) in reshaping the TME and enhancing anti-tumour immune responses, providing multi-dimensional and in-depth theoretical basis and practical directions for future cancer immunotherapy.

To investigate the role of PANoptosis activation in anti-melanoma differentiation-associated protein 5 (MDA5) antibody-positive dermatomyositis (anti-MDA5+ DM). Transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) from 40 patients with anti-MDA5+ DM and 10 healthy controls (HCs) was performed. The PANoptosis signature score was constructed using single sample gene set enrichment analysis based on the mean enrichment scores of the pyroptosis, apoptosis and necroptosis gene sets, and the clinical associations of the PANoptosis signature score in patients with anti-MDA5+ DM were evaluated. PANoptosis markers were analysed via western blotting, and the regulatory mechanism of PANoptosis activation was studied in Jurkat cells in vitro. Transcriptomic profiling demonstrated overactivation of the PANoptosis signalling pathway in patients with anti-MDA5+ DM. The PANoptosis signature score was positively correlated with inflammatory markers, type 1 interferon (IFN) signature score, disease severity and poor prognosis in patients with anti-MDA5+ DM. Z-DNA binding protein 1 (ZBP1) was identified as a key PANoptosis-related gene in anti-MDA5+ DM. PANoptosis markers, including P-MLKL, GSDMD-N, cleaved caspase-8, cleaved caspase-3 and cleaved caspase-7, were significantly upregulated in T cells from patients with anti-MDA5+ DM. Functional assays demonstrated that IFN-β induced PANoptosis activation in T cells in vitro, which was significantly attenuated following ZBP1 knockdown. PANoptosis overactivation was associated with disease severity and prognosis in anti-MDA5+ DM. Our findings indicated that IFN-β triggered ZBP1-mediated PANoptosis in T cells, highlighting PANoptosis as a novel potential therapeutic target for anti-MDA5+ DM.

This study was a post hoc analysis of a Phase III trial (NCT04839016), which aims to investigate whether early response to vunakizumab can predict long-term efficacy in plaque psoriasis patients. A total of 461 plaque psoriasis patients receiving vunakizumab treatment were included for analysis. Early response to vunakizumab was defined by patients achieving a psoriasis area and severity index (PASI) 50 at week (W) 2. Efficacy analysis included PASI 75/90/100 and static physician's global assessment (sPGA) 0/1 response rates in both groups. Safety was analysed in both groups. At W2, 249 patients achieved an early response; 212 did not. At W12, higher proportions of patients in the early response group achieved PASI 75/90/100 and sPGA 0/1 versus the without early response group (98.4% vs. 88.2%, 88.0% vs. 66.0%, 50.2% vs. 25.0%, 84.7% vs. 64.6%, respectively; all p < 0.001). The early response group had higher proportions of patients who maintained PASI 75/90/100 and sPGA 0/1 from W12 to W52 versus the without early response group (88.8% vs. 76.4%, 74.7% vs. 54.7%, 39.4% vs. 20.8%, 68.7% vs. 54.2%, respectively; all p < 0.001). Multivariate logistic regression analysis showed that early response to vunakizumab was independently associated with PASI 100 response at W52 (odds ratio = 1.772, p = 0.027). The incidence of adverse events was similar between groups. Patients with moderate-to-severe plaque psoriasis receiving vunakizumab show a favourable clinical response, regardless of achieving early response or not. Particularly, patients with early response at Week 2 are significantly more likely to achieve better long-term treatment outcomes.

Systemic lupus erythematosus (SLE) is an autoimmune disease marked by dysregulated T cell responses and elevated pro-inflammatory cytokines such as IL-17A. Identifying reliable biomarkers could improve diagnosis and understanding of SLE pathogenesis. This study aimed to characterise CD161 and CCR6 expression on peripheral T cells in SLE and evaluate their diagnostic potential. Peripheral blood mononuclear cells were obtained from 34 new onset SLE patients, 26 primary Sjögren's syndrome (pSS) patients and 20 age- and sex-matched healthy controls. Flow cytometry profiled CD4⁺ and CD8⁺ T cells for CD161, CCR6, CXCR3 and intracellular IL-17A. Standard laboratory assays measured complete blood counts, CRP, ESR, complement, immunoglobulins and autoantibodies. Statistical analyses included Student's t-test, Mann-Whitney test, or ANOVA for group comparisons, Spearman's correlation and receiver operating characteristic (ROC) curve analysis with cut-offs determined by the Youden index. A distinct CD4⁺CD161⁺CCR6⁺ subset was present in healthy blood and showed significantly higher IL-17A than CD161⁺CCR6^- or CD161^-CCR6⁺ cells. In SLE patients, the frequency of CD4⁺CD161⁺CCR6⁺ cells was markedly increased compared to healthy controls (median 18.0% vs. 9.2%, p < 0.001) and CD4⁺CD161⁺ alone was also elevated (p < 0.05). ROC analysis distinguishing SLE from healthy controls yielded AUCs of 0.993 for CD4⁺CD161⁺, 0.774 for CD4⁺CD161⁺CCR6⁺ and 0.526 for CD4⁺CCR6⁺. Using pSS as disease controls, CD4⁺CD161⁺CCR6⁺ cells achieved an AUC of 0.868. CD161⁺CCR6⁺ CD4⁺ T cells are enriched for IL-17A and significantly elevated in early SLE, demonstrating moderate diagnostic accuracy. These findings support their potential role as novel blood biomarkers for SLE.