Frontiers in Immunology最新文献

This review explores the alterations in natural killer (NK) cell function in acute myeloid leukemia (AML) and their implications for disease progression and therapeutic outcomes. As key effectors of innate immunity, NK cells are critical in recognizing and eliminating malignant cells. In AML, however, NK cells frequently exhibit numerical and functional deficiencies, resulting in compromised immunosurveillance that facilitates tumor immune escape and disease advancement. We systematically examine the application of single-cell omics technologies in AML research to elucidate the omics profiles and phenotypic distribution of NK cells within the leukemic microenvironment, characterizing their dysfunctional state by upregulated inhibitory receptors, downregulated activating signals, an altered cytokine milieu, and complex cellular crosstalk within the bone marrow (BM) niche. Furthermore, this article correlates functional dynamics of NK cells with conventional and emerging treatments, including CAR-NK immunotherapy, underscoring their potential role in disease monitoring and prognostic stratification. We also discuss promising NK cell-based immunotherapeutic strategies for AML, emphasizing the potential of modulating or engineering NK cells to enhance antitumor immunity. A deeper understanding of NK cell biology and regulatory mechanisms in AML is essential for developing novel immunotherapies and improving patient prognosis.

Objective: To systematically compare the differences in immune characteristics among three populations (normal group, high-risk group, and esophageal cancer [EC] patients group) and construct a predictive model based on immune metrics, thereby exploring its value in EC risk assessment and early diagnosis.

Methods: A total of 440 participants were enrolled, including 173 normal individuals, 162 high-risk individuals, and 105 EC patients. Peripheral blood samples were collected, and 75 immune metrics were detected using flow cytometry. First, 21 highly correlated indicators were eliminated through the Pearson correlation matrix (|r|≥0.7), leaving 54 indicators for further analysis. Multivariate analysis of variance (MANOVA) was used to assess the effect of EC grouping on immune metrics, adjusting for gender and age. Significant indicators were analyzed using analysis of covariance (ANCOVA) and the false discovery rate (FDR). Stratified sensitivity analysis was conducted to verify the robustness of the results. Finally, a predictive model was built using 12 key immune metrics, and 10 covariates. The model performance was evaluated by 10-fold cross-validation, neural network algorithm, accuracy, Kappa value, and area under the receiver operating characteristic curve (AUC).

Results: MANOVA showed that EC grouping had a significant overall impact on the 54-immune metrics (Pillai = 0.585, P < 2.2×10^{^-16}). After ANCOVA and FDR correction, 12 immune metrics with significant inter-group differences were identified (P' < 0.05), including Tcm CD4⁺ T cells, Naive CD8⁺ T cells, Tem CD8⁺ T cells, and FB CD8⁺ T cells. Stratified sensitivity analysis confirmed stable differences in key indicators (FB CD8⁺ T cells and Act NK cells) remained stable among subgroups. The neural network predictive model exhibited excellent discriminative efficacy: the overall cross-validation accuracy was 81.2%, the Kappa value was 0.709, and the AUC values for pairwise comparisons among the three populations were all higher than 0.90 (0.905 to 0.927).

Conclusion: This study demonstrates distinct and stable immune profiles across EC risk groups. The immune-based machine learning model effectively differentiates normal, high-risk, and cancer populations, offering a promising non-invasive tool for early risk assessment and screening of esophageal cancer.

Autoimmune diseases arise from immune system dysfunction, in which immune cells erroneously attack the body's own tissues, leading to systemic disorders or localized pathological changes. The number of patients with autoimmune diseases is gradually increasing, and patients with relapsing-refractory conditions face the dilemma of inadequate efficacy when treated with conventional medications and biologic agents. However, bispecific T-cell engagers (BiTEs) and chimeric antigen receptor T-cell (CAR-T) therapy, as emerging immunotherapeutic strategies, have opened up new possibilities for the treatment of these diseases. BiTEs activate T-cell-mediated immune responses by simultaneously targeting T cells and tumor-associated antigens, while CAR-T therapy involves genetic engineering of T cells to enable them to specifically recognize and eliminate target cells. Both therapeutic approaches have demonstrated unique advantages and potential in the treatment of rheumatic immune diseases, providing novel insights and methods to address this challenging clinical issue. This article will conduct a comparative analysis of the applications of CAR-T cell therapy and BiTEs in rheumatic immune diseases, exploring their mechanisms of action, therapeutic efficacy, safety profiles, and future development prospects, with the aim of providing references for clinical practice.

Graves' disease (GD) is a common autoimmune thyroid disorder and is often accompanied by Graves' orbitopathy (GO), an inflammatory eye disease that can significantly reduce the quality of patients' life. Despite understanding of GD and GO has progressed, the mechanisms driving disease progression remain incompletely defined. Emerging evidence highlights extracellular vesicles (EVs), particularly exosomes, as important mediators of immune regulation and tissue remodeling in autoimmune disorders, including GD and GO. This review summarizes current knowledge of EVs biogenesis and molecular compositions, highlighting their contributions to GD and GO pathogenesis. We also discuss the diagnostic and prognostic potential of EV-associated miRNAs and proteins, and consider findings from other immune-mediated ocular diseases to place these observations in a broader immunopathological context. Overall, EVs appear to be actively involved in GD and GO and may serve as useful tools for disease monitoring and therapy development. Nonetheless, challenges such as methodological variability and limited functional validation remains. Standardized protocols and larger, multicenter studies are needed to support the clinical translation of EV-based approaches.

Background: Previous studies have demonstrated that hepatocyte growth factor (HGF) is implicated in treatment resistance in rheumatoid arthritis (RA). This study aimed to elucidate the mechanistic role of HGF in synovial inflammation and assess the therapeutic potential of targeting the HGF-c-Met axis.

Methods: Plasma HGF levels were measured in 66 RA patients. The expression of HGF and its receptor, c-Met, in synovial tissue was assessed using publicly available single-cell RNA sequencing data and immunostaining. The effects of HGF on synovial fibroblasts were examined through bulk RNA sequencing, immunostaining, and quantitative PCR. The therapeutic efficacy of the c-Met inhibitor savolitinib was evaluated in a mouse model of arthritis.

Results: Plasma HGF levels were significantly elevated in RA patients (p = 0.0003) and correlated with Disease Activity Score 28-ESR (r = 0.367, p = 0.002). Single-cell analysis and immunostaining revealed that HGF was predominantly expressed in monocytes and fibroblasts, while c-Met expression was restricted to synovial fibroblasts. RNA sequencing indicated that HGF stimulation upregulated key inflammatory markers, including IL-6 and HGF itself, in synovial fibroblasts, establishing an inflammatory feedback loop. In vivo, inhibition of the HGF-c-Met pathway with savolitinib significantly suppressed arthritis development and reduced synovial inflammation. Additionally, activation of Toll-like receptor 4 and 5 activation induced HGF production in human monocytes, which may amplify IL-6-mediated inflammation.

Conclusion: HGF primarily acts on synovial fibroblasts, driving an IL-6-mediated inflammatory amplification loop that may contribute to therapeutic resistance in RA. Targeting the HGF-c-Met pathway could represent a novel strategy for overcoming treatment refractoriness in RA.

Introduction: Human Dental Pulp Stromal Cells (hDPSCs) of neural-ectodermal origin hold immunomodulatory properties which make them a source for MSC-based therapies for the treatment of autoimmune diseases.

Methods: In this study hDPSCs were exposed to inflammatory conditions mimicked by co-culture with Peripheral Blood Mononuclear Cells activated with anti-CD3/CD28 (aPBMCs) or treatment with Conditioned Medium (CM) from aPBMCs with or without the addition of a specific IL6 receptor (IL6R) inhibitor. To assess IL-6 effects on PD-L1 expression, hDPSCs were treated with IL-6/sIL6R complex and the activation of IL-6 trans-signalling was investigated. The functional role of IL-6 in modulating PD-L1 protein stability was further confirmed by treating hDPSCs with a proteasome inhibitor.

Results: Our results highlighted that hDPSCs exposed to different inflammatory conditions activate Fas/FasL and PD1/PD-L1 pathways. Moreover, hDPSCs modulate inflammatory cytokines release of aPBMCs from Rheumatoid Arthritis (RA) patients. However, the inflammatory milieu induced the upregulation of IL-6 by hDPSCs, which was demonstrated to be strongly correlated to PD-L1 expression, suggesting its involvement in supporting their immunoregulation. Our data demonstrated that the activation of the IL6/JAK/STAT3 trans-signaling pathway in hDPSCs through stimulation with the IL6/sIL6R complex leads to an increase in PD-L1 protein levels, but not PD-L2, via proteasome inhibition.

Conclusion: Our study demonstrates the activation of the IL-6/PD-L1 axis in response to inflammatory conditions and underscores its potential significance in autoimmune diseases since a dysfunction of this mechanism could lead to the onset and progression of chronic inflammatory disorders.

Introduction: Atherosclerosis can trigger various cardiovascular and cerebrovascular diseases with complex pathogenesis. Macrophage proliferation, inflammatory responses, and lipid phagocytosis, which induce foam cell formation and accumulation, are critical in the development of early atherosclerotic lesions. The role of 3-Hydroxystearic acid (C18-3OH), a recently identified gut microbiota-derived metabolite, in atherosclerosis has not yet been clarified. This study aimed to investigate the role of the ALKBH5/PAX-8/ABCA1 pathway in C18-3OH-mediated regulation of macrophage cholesterol efflux and atherosclerosis and explore novel mechanisms of ABCA1 regulation from the perspective of m6A modification.

Methods: RT-qPCR and Western blotting were used to detect gene and protein expression, respectively. ChIP-Seq was used to screen PAX-8 target genes, and ChIP-qPCR was used to validate PAX-8 binding to ABCA1. The SRAMP platform was used to predict m6A modification sites in PAX-8 mRNA sequences. Methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR) was used to measure m6A modification levels of PAX-8 mRNA in foam cells. UHPLC-OEMS untargeted metabolomics were used to analyze differential fatty acid metabolites in an atherosclerotic mouse model. Specific kits were used to detect serum liver function markers (aspartate transaminase, AST; alanine aminotransferase, ALT), renal function markers (serum creatinine, Scr; blood urea nitrogen, BUN), and lipid profiles (HDL-C, TG, LDL-C, TC). Aortic sinus sections were prepared, and H&E, Oil Red O, and Masson staining were used to evaluate atherosclerotic plaques.

Results: The results demonstrated that C18-3OH promoted cholesterol efflux in foam cells and alleviated lipid accumulation by upregulating ABCA1 expression. C18-3OH inhibited ALKBH5, increased PAX-8 mRNA m6A modification and PAX-8 expression, and upregulated ABCA1 to enhance cholesterol efflux. Serum metabolomics revealed reduced C18-3OH levels in high-fat diet-fed apoE-/- atherosclerotic mice. C18-3OH suppressed aortic ALKBH5 expression, elevated m6A modification of PAX-8 mRNA, and increased PAX-8 and ABCA1 expression. Furthermore, C18-3OH improved lipid metabolism and reduced the atherosclerotic plaque area in apoE-/- mice.

Discussion: This study clarifies the impact and mechanisms of gut microbiota-derived C18-3OH on atherosclerosis progression, providing novel strategies for the precise prevention and treatment of atherosclerosis.

Background: Thrombopoietin receptor agonists combined with anti-thymocyte globulin (ATG) and cyclosporine (CsA) are the standard immunosuppressive therapy (IST) for severe/very severe aplastic anemia (SAA/VSAA). However, early response rates remain suboptimal. Cyclophosphamide (CTX) has shown efficacy in relapsed/refractory AA. Therefore, we designed a clinical trial to evaluate low-dose CTX combined with the standard IST as a first-line treatment for SAA/VSAA to improve early response rates.

Methods: This study was a single-arm, prospective, phase II clinical trial using a Simon's two-stage design, and 43 patients were enrolled. The primary endpoint was the overall response rate (ORR) at 3 months. Newly diagnosed SAA/VSAA patients received a combination treatment as follows: porcine ATG at 25 mg/kg/day from days 1 to 5, CsA at 3-5 mg/kg/day continuously, hetrombopag at 15 mg/day starting from day 1 and continued for 6 months, low-dose CTX at 20 mg/kg/day on days 29-30 and days 43-44.

Results: All 43 patients achieved the primary endpoint, demonstrating 3-month and 6-month ORR of 65.1% (28/43) and 69.8% (30/43) respectively. Complete response (CR) rates were 9.3% (4/43) at 3-month and 27.9% (12/43) at 6-month. CTX associated toxicities comprised 100% grade 1-2 gastrointestinal reactions, grade 3-4 neutropenia in 62.8% of patients (median duration 6 days, range 4-33). Infectious events occurred in 60.5% (26/43) of patients within the first 3 months of treatment, while no mortality observed during this period.

Conclusions: Low-dose CTX combined with standard IST appears to improve the early response rate in SAA/VSAA patients with manageable toxicity.

Introduction: Natural killer (NK) cells are innate lymphocytes that kill tumor cells by natural cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC). Human NK cells mediate the latter process exclusively by the IgG Fc receptor CD16 (FcγRIIIA). Cell surface levels of this activating receptor are tightly regulated by the metalloprotease ADAM17, which cleaves CD16 upon NK cell activation or cellular stress. We have reported that Medi-1, a fully human IgG1 mAb, blocks ADAM17, and its Fc region is simultaneously engaged by CD16, inducing and prolonging its signaling, which synergizes with cytokine stimulation, such as IL-15. To exploit these distinctive features of Medi-1 while also addressing limitations of the mAb, such as the varied affinity by which CD16 binds to it due to receptor polymorphisms and the risk of broadly blocking ADAM17 activity, we engineered Targeted ADAM17 Blocker CD16 (TAB16).

Methods: TAB16 was generated with a camelid heavy-chain variable domain specific to CD16 linked to a single-chain variable fragment derived from Medi-1. TAB16 was further modified by the linkage of an IL-15 moiety to generate TAB16/15. Primary human NK cells were treated with TAB16 or TAB16/15 and evaluated for proliferation by cell dilution dye, ADAM17 blocking, activation marker expression, and cytotoxicity against ovarian cancer cell lines in real-time by IncuCyte assays.

Results: The TAB16 bispecific engager targeted NK cells and blocked ADAM17. A novel feature of TAB16 is its dual functionality, as it synergizes with IL-15 to enhance NK cell activation and proliferation and targets ADAM17 overexpressed on cancer cells to induce ADCC. TAB16 is a modifiable backbone to which additional functional components can be added, such as IL-15 (TAB16/15) for consolidated and multifaceted activity.

Discussion: Our ADAM17-engaging platform offers a unique approach for targeted ADAM17 inhibition to augment the anti-tumor function of endogenous and therapeutic NK cells.

Malignant tumors of the digestive tract are a major global health burden, characterized by high incidence and mortality rates, limited treatment options for advanced patients, and poor prognosis. Ferroptosis is an iron-regulated form of cell death driven by lipid peroxide (LPO) accumulation, and it is closely linked to the occurrence and progression of various cancers. Ferroptosis plays a critical role in the proliferation, metastasis, drug resistance, and microenvironment regulation of digestive tract cancer. This article will systematically examine the dual roles of ferroptosis through the core concepts of mechanism analysis, microenvironment regulation, and immune interactions, while exploring the therapeutic potential of targeting ferroptosis in the treatment of gastrointestinal malignancies.