Frontiers in Immunology最新文献

Objective: Lymphatic vessels are present in the capsule of hepatocellular carcinoma (HCC) at an early stage, but their value in the prognosis remains unclear. The study aimed to evaluate the prognostic impact of lymphatic vessels in the tumor capsule on patients with HCC at Barcelona Clinic Liver Cancer (BCLC) stages 0-A. This is one of the first studies to investigate the tumor capsule specifically.

Methods: This retrospective study included HCC patients at BCLC stages 0-A, who underwent radical liver resection between January 2017 and December 2020. Lymphatic vessel density (LVD) in the tumor capsule was determined by immunohistochemistry using anti-D2-40. Patients were stratified into the high and low LVD groups. Their overall survival (OS) and recurrence-free survival (RFS) were analyzed. The potential risk factors affecting survival and for predicting microvascular invasion (MVI) or satellite nodules were analyzed using Cox regression analysis and logistic regression analysis, respectively.

Results: A total of 212 patients were included (180 male and 142 patients < 60 years old). The 1, 3, and 5-year OS were 76.5%, 52.9%, and 41.2% in the high LVD group, versus 94.4%, 76.4%, and 69.0% in the low LVD group (P = 0.013). The 1, 3, and 5-year RFS were 30.6%, 30.6%, and 30.6% in the high LVD group, versus 72.5%, 52.2%, and 38.7% in the low LVD group (P = 0.014). High LVD in the tumor capsule was an independent risk factor for worse OS (HR = 2.145, 95% CI: 1.096-4.197, P = 0.026) and RFS (HR = 2.506, 95% CI: 1.197-5.243, P = 0.015), and also associated with the onset of MVI (OR = 8.493, 95% CI: 2.314-31.174, P = 0.001) and satellite nodules (OR = 5.755, 95% CI: 1.340-24.718, P = 0.019).

Conclusions: High LVD in the tumor capsule was associated with worse OS, RFS, and intrahepatic spread (MVI and satellite nodules) in patients with HCC at BCLC stages 0-A after liver resection. Our findings suggest that assessing LVD in the tumor capsule could serve as a useful tool in predicting postoperative prognosis and guiding personalized treatment strategies for patients with early-stage HCC.

Background: Coagulation is an important physiological process for the body to cope with vascular injury, involving platelet activation, coagulation factor cascade reaction and fibrin formation. The role of the coagulation system in inflammatory and degenerative diseases has received increasing attention in recent years. However, its impact for osteoarthritis remains to be well investigated.

Methods: The GEO database provided us with microarray data that included osteoarthritis and normal samples. The Genecards database provided coagulation-related genes. Protein interaction network analysis, machine learning, and screening for differentially expressed genes were used to identify coagulation-related core genes relevant to osteoarthritis. Coagulation-related osteoarthritis subtypes were identified by clustering analysis. Enrichment analysis and immune infiltration analysis revealed the potential mechanism of coagulation-related genes promoting osteoarthritis progression. The screened core genes were further validated by chondrocyte experiments.

Result: We successfully screened the coagulation-related genes COL3A1 and MMP1 as core genes for osteoarthritis diagnosis. Both nomogram and diagnostic model constructed based on them have excellent diagnostic value, while OA samples can be classified into different subtypes. Immune infiltration study confirmed enrichment analysis's finding that COL3A1 could affect the course of osteoarthritis by controlling immunological pathways. Basic research confirms that overexpression of COL3A1 inhibits proliferation and viability of chondrocytes and promotes senescence and damage. We confirmed that COL3A1 is an intervention target for osteoarthritis.

Conclusion: Our study identifies osteoarthritis subtypes associated with coagulation and reveals the regulatory role of COL3A1 on chondrocytes in inflammatory environment. It offers fresh perspectives on osteoarthritis management.

Head and neck squamous cell carcinoma (HNSCC) develops within a chronically inflamed tumor microenvironment (TME) where metabolic reprogramming and immune suppression tightly co-evolve. A prominent example is the tryptophan-kynurenine (Trp-Kyn) pathway, initiated by indoleamine 2,3-dioxygenase 1/2 (IDO1/IDO2) and tryptophan 2,3-dioxygenase (TDO2), which converts tryptophan into kynurenine and downstream metabolites that engage stress-response programs and aryl hydrocarbon receptor (AhR) signaling. In HNSCC, Trp-Kyn enzymes are inducible by interferons and oncogenic cues and are distributed across malignant cells as well as cancer-associated fibroblasts, endothelial cells and tumor-associated myeloid populations, generating spatially restricted "Trp-low/Kyn-high" immunometabolic niches. Within these niches, tryptophan starvation and kynurenine-driven signaling converge to suppress effector T-cell expansion, promote regulatory T-cell programs, undermine dendritic-cell priming and reinforce tolerogenic myeloid states, collectively fostering T-cell exhaustion and reduced sensitivity to PD-1/PD-L1 blockade. Emerging bulk, single-cell and spatial multi-omics studies support the idea that pathway activity is compartmentalized rather than uniform, providing a mechanistic rationale for the limited performance of first-generation IDO1 inhibitor strategies in unselected clinical settings. This mini-review synthesizes current evidence on Trp-Kyn microdomains in the HNSCC TME and discusses therapeutic opportunities that move beyond single-enzyme inhibition, including dual IDO1/TDO2 targeting, AhR antagonism and biomarker-guided combination regimens to restore antitumor immunity.

[This corrects the article DOI: 10.3389/fimmu.2025.1730184.].

Introduction: Cytotoxic T lymphocytes (CTLs, mainly CD8⁺ T cells) are the primary killer cells in the tumor microenvironment (TME). This study investigates the expression of LAG-3 in the TME of cervical cancer and its regulatory role in CD8⁺ T cell function.

Methods: Cervical tissue pathological sections and fresh cervical tissues were collected from patients with cervical cancer, patients with high-grade squamous intraepithelial lesion (HSIL), and patients who underwent hysterectomy for non-cervical diseases (without a history of other tumors). Immunohistochemistry, Western blotting, quantitative real-time PCR, and fluorescence imaging techniques were used to analyze the expression of LAG-3 in the cervical cancer TME and its correlation with clinical tumor stage, differentiation grade, lymph node metastasis status, and lymphovascular space invasion. A cell co-culture system and a cervical cancer mouse model were established to evaluate the effects of lag-3 on tumor growth and changes in CD8⁺ T cell function.

Results: LAG-3 is highly expressed in the tumor microenvironment (TME) of cervical cancer, with its expression level increasing as the tumor stage progresses: the lower the degree of differentiation, the higher the LAG-3 expression; LAG-3 expression is also elevated in cases with lymph node metastasis and lymphovascular space invasion. In vivo mouse models confirmed that lag-3 inhibits CD8⁺ T cells from expressing Ki67, T-bet, TNF-α, IFN-γ, and IL-2. Furthermore, we found that lag-3 not only suppresses the differentiation of naive CD8⁺ T cells into central memory T cells (TCM) but also inhibits the differentiation of TCM into effector memory T cells (TEM), a subset with stronger anti-tumor effector functions. A similar phenomenon was observed in cell co-culture experiments.

Discussion: We confirmed that LAG-3 is highly expressed in cervical cancer tissues and is closely correlated with clinical stage, differentiation grade, lymph node metastasis, and lymphovascular space invasion. LAG-3 may inhibit the function of CD8⁺ T cells in the cervical cancer TME, thereby promoting the progression of cervical cancer.

Actin-binding proteins play a critical role in regulating the dynamic rearrangement of the actin cytoskeleton, which is essential for maintaining cellular homeostasis and facilitating various processes in eukaryotic cells. Cofilin-1 (Cfl1), an actin-binding protein, promotes the severing and depolymerization of actin filaments. To investigate the function of Cfl1 in mast cells, we generated Mcpt5-Cre-nf-Cfl1^fl/fl knock-in mice, expressing a non-functional form of Cfl1 (nf-Cfl1) instead of wildtype Cfl1 under the control of the connective tissue mast cell (CTMC)-specific promoter mast cell protease 5 (Mcpt5). Expression of nf-Cfl1 resulted in the complete absence of CTMCs. Notably, normal numbers of basophils were observed, in contrast to other mast cell-deficient mice. Interestingly, an inducible knock-in of nf-Cfl1 in mature mast cells did not affect the survival of mature mast cells. The Mcpt5-Cre-nf-Cfl1^fl/fl mice lacking CTMCs showed impaired induction of systemic anaphylaxis. However, they remained fully susceptible to 1-fluoro-2,4-dinitrobenzene-induced contact hypersensitivity and imiquimod-induced psoriasis-like dermatitis. In addition, clearance of vaccinia virus skin infection was unaltered. Thus, this study demonstrates that CTMCs are not essential in these inflammatory skin diseases. Deviating results in some other mast cell-deficient models suggest that the concomitant lack of basophils or residual CTMCs in these mouse models influence disease outcome. Taken together, the complete absence of CTMCs and the preserved presence of basophils in Mcpt5-Cre-nf-Cfl1^fl/fl mice establishes this model as a valuable tool for studying the specific role of CTMCs in different diseases.

Objectives: Aiming to evaluate the predictive value of high-resolution computed tomography (HRCT) features for identifying acute/subacute progression in patients with polymyositis/dermatomyositis (PM/DM)-associated interstitial lung disease (ILD), and to develop a risk stratification algorithm based on clinico-radiologic parameters.

Methods: This retrospective cohort study included 282 patients with PM/DM who underwent HRCT from January 2020 to December 2024. Baseline clinical data and HRCT imaging characteristics were systematically collected. Over time, 140 patients with PM/DM-ILD were followed. HRCT scores and imaging patterns were assessed, and cases of acute/subacute ILD progression were documented during the follow-up period. Penalized Cox regression (LASSO) was conducted to identify independent risk factors associated with disease progression and to develop a risk stratification method. The concordance index (C-index), net reclassification improvement (NRI), integrated discrimination improvement (IDI) and decision curve analysis (DCA) were used to evaluate the discriminative ability of this stratification. Algorithm performance was assessed using calibration plots to evaluate agreement between predicted and observed risks.

Results: During a median follow-up duration of 5.69 months (IQR, 1.77-5.91 months), 56 (40.0%) patients experienced acute/subacute ILD progression. The HRCT score was considered an independent predictor of acute/subacute progression in patients with PM/DM-ILD. A newly developed risk stratification scheme, according to thresholds of HRCT score, imaging classification (organizing pneumonia [OP] vs. non-OP patterns), and anti-MDA5 antibody status, demonstrated good predictive ability for identifying patients at risk of progression. In combination with clinical parameters, the integrated predictive algorithm significantly outperformed traditional clinical risk algorithm, with significant enhancements in C-index (to 0.764). The incremental predicted value was demonstrated by improved NRI (0.470), IDI (0.218), and DCA metrics.

Conclusion: A high HRCT score is an independent predictor of acute/subacute progression in patients with PM/DM-ILD. Incorporating clinical parameters into the imaging-based algorithm significantly improves its predictive accuracy for progressive disease.

Lung cancer is the leading cause of cancer-related mortality globally, with non-small cell lung cancer (NSCLC) accounting for the majority of cases. For resectable early-stage NSCLC, surgery and adjuvant chemotherapy remain the standard treatments, but the recurrence rate is high, and long-term survival outcomes are suboptimal. In recent years, immunotherapy, particularly immune checkpoint inhibitors (ICIs), has revolutionized the treatment of advanced NSCLC and is gradually being extended to early-stage disease. Neoadjuvant immunotherapy, as an emerging strategy, aims to activate anti-tumor immune responses preoperatively, eliminate microscopic metastases, and downstage tumors, thereby improving surgical resectability and enhancing long-term survival for patients. Several clinical trials have demonstrated that neoadjuvant immunotherapy, either alone or in combination with chemotherapy, significantly increases the major pathological response (MPR) and pathological complete response (pCR) rates, translating into improvements in event-free survival (EFS). However, this promising therapeutic approach faces numerous challenges, including the lack of precise biomarkers for efficacy prediction, unclear treatment strategies for patients with driver gene-positive tumors, primary and secondary resistance, management of immune-related adverse events (irAEs), and the complexities of post-treatment efficacy evaluation. This review aims to comprehensively summarize the latest clinical evidence on neoadjuvant immunotherapy for lung cancer, delve into the main challenges and opportunities encountered in clinical practice, and explore its future directions, including novel combination therapies, personalized treatment strategies, and the application of innovative technologies, with the goal of optimizing clinical management for early-stage lung cancer patients and advancing research in this field.

We previously demonstrated that phosphatidylserine liposomes (PS-L) reduce inflammation and enhance intracellular killing of Mycobacterium abscessus (Mab) in infected human macrophages, with functional or pharmacologically inhibited cystic fibrosis conductance regulator (CFTR). Here, we evaluated the in vitro therapeutic potential of PS-L in macrophages from people with cystic fibrosis (pwCF), either under therapeutic regimen or not with CFTR modulator therapy Elexacaftor/Tezacaftor/Ivacaftor (ETI). Results show that PS-L exerted an anti-inflammatory effect in Mab infected macrophages, reducing TNF-α and IL-1β production and inducing IL-10 release at early and late time points, respectively. In addition, PS-L significantly increased antimycobacterial activity in macrophages from pwCF either undergoing or not ETI regimen. Importantly, in ETI-ineligible pwCF, PS-L alone still was capable to enhance a significant antimycobacterial response. Finally, PS-L combined with amikacin further enhanced intracellular bacterial clearance compared to single treatments. Altogether, these findings support PS-L as a promising host-directed therapy against Mab infection, particularly for pwCF who cannot benefit from ETI.

Objective: This study aimed to evaluate the association between intravenous immunoglobulin (IVIG) treatment and pregnancy outcomes among women with recurrent pregnancy loss (RPL) in China.

Methods: We conducted a retrospective cohort study involving RPL pregnant women who delivered at the Lanzhou University Second Hospital between April 2023 and August 2024. Participants were categorized into a treatment group (received IVIG during pregnancy) and a control group (not received). The pregnancy outcomes were live birth rate (LBR), preterm birth, birth weight, and neonatal unit admission. RPL pregnant women exposed to IVIG were matched to unexposed in a 1:1 ratio with propensity score matching (PSM), using the nearest neighbor matching. Multivariable logistics regression was used to assess the association between IVIG use during pregnancy and pregnancy outcomes. We further conducted a stratified analysis based on the mean daily dose and the gestational age at the initiation of IVIG administration.

Results: A total of 504 RPL pregnant women were included, of whom 173 received IVIG during pregnancy and 331 did not. After PSM, 276 patients were analyzed with balanced baseline characteristics. The primary analysis showed that IVIG treatment during pregnancy was associated with a significantly higher LBR compared to controls (60.1% vs. 44.9%; adjusted OR [aOR]=1.960). This association remained significant after excluding cases with embryonic abnormal karyotypes (64.3% vs. 46.3%; aOR=2.187). Stratified analyses indicated that a mean daily IVIG dose <20 g was associated with improved LBR (aOR=2.484), and the benefit persisted after excluding abnormal karyotypes (aOR=3.000). Additionally, initiation of IVIG between 6-12 weeks' gestation yielded higher LBR (72.8% vs. 44.9%; aOR=3.253), especially among participants without abnormal karyotypes (76.6% vs. 46.3%; aOR=3.757). No significant associations were observed between IVIG use and preterm birth rate, birth weight, or neonatal unit admission rate.

Conclusions: IVIG use during pregnancy was associated with a significantly higher LBR among RPL women, particularly when initiated between 6-12 weeks of gestation and administered at a dose <20 g/d; these associations remained robust after excluding cases with abnormal karyotypes. These findings suggest that IVIG may be an effective immunological intervention for improving pregnancy outcomes in selected RPL patients.