ImmunoTargets and Therapy最新文献

Purpose: Beyond its direct anticancer effects in breast cancer (BC), vitamin D₃ (VD₃) also modulates tumor progression and metastasis through immune mechanisms. T-helper 17 (Th17) cells may play a key role in these effects. This study investigates how VD₃ influences Th17 differentiation in 4T1 and 67NR murine BC models.

Methods: Calcitriol or tacalcitol was administered to young and aged mice bearing 4T1 or 67NR tumors. Tumor growth, angiogenesis, and metastasis were evaluated. CD4⁺ lymphocytes isolated from tumors and other tissues were analyzed by flow cytometry for IL-17 and osteopontin (OPN, Spp1) receptors. CD4⁺ splenocytes were separated; gene expression was assessed using qPCR, and protein levels by Western blotting, ELISA. CD3⁺CD4⁺ splenocytes were ex vivo differentiated into Th17 cells with blockade of CD29, CD51, and CD44, followed by flow cytometric analysis of IL-17 and IFNγ expression.

Results: Tacalcitol increased metastasis in young mice but decreased it in aged mice with 4T1 tumors. Th17 cell levels in the lungs increased in young mice treated with tacalcitol but declined in aged counterparts. IL-17⁺ and IFNγ⁺ Th17 cells increased upon differentiation from splenocytes of treated mice. CD29 promoted IL-17 expression in tacalcitol-treated mice, while CD51 and CD44 had opposing effects. CD51 blockade reduced IFNγ⁺ Th17 cells in both treatment groups. Spp1 expression increased in CD4⁺ lymphocytes, and OPN levels were elevated in induced Th17 cells from tacalcitol-treated young mice, suggesting a role in Th17 activation.

Conclusion: CD29 stimulates IL-17 expression in response to tacalcitol, while CD51 and CD44 exert opposing effects. CD51 also mediates IFNγ expression. VD₃-induced modulation of IL-17 and IFNγ in Th17 cells may influence their pro- or anticancer function.

Background: Rapid bone loss after fracture elevates the risk of subsequent fractures, but the mechanisms remain unclear. IL-6, a key cytokine involved in fracture healing, is markedly upregulated during the immune response after fracture; however, its role in systemic skeletal deterioration remains poorly defined.

Methods: In this study, we employed label-free proteomics to identify candidate mediators in vertebral samples following fracture. Next, osteocyte siRNA knockdown and Stattic (STAT3 phosphorylation inhibitor) inhibition were used to investigate IL-6 related signaling pathways. Subsequently, indirect co-cultures of osteocyte with osteoclast or osteoblast were used to evaluate the effects of the IL-6 pathway on bone resorption and formation. Furthermore, fractured mice were treated with MR16-1 (monoclonal anti-mouse IL-6 receptor antibody) or Stattic. Then, trabecular and cortical bone in vertebrae and femur were evaluated at 4, 14, and 28 days post-fracture, including histological analysis of p-STAT3⁺ osteocyte, RANKL expression, and bone formation/resorption markers.

Results: In vitro, IL-6 dose-dependently elevated RANKL and p-STAT3 levels in osteocyte and promoted osteoclast activity in co-culture. These effects were suppressed by Stattic and replicated by STAT3 knockdown. In contrast, co-culture of osteocyte with osteoblast exhibited no significant alterations in osteogenic marker expression upon IL-6 exposure, suggesting negligible effects on osteoblast activity. In vivo, MR16-1 reduced trabecular bone loss in the vertebrae and femur after fracture. It also diminished p-STAT3⁺ osteocyte, reduced RANKL expression, and suppressed osteoclast activity without impairing osteoblastogenesis. And Stattic produced a comparable reduction in systemic bone loss and osteoclast overactivation.

Conclusion: This study demonstrates that IL-6 drives osteoclast-mediated bone resorption via STAT3-dependent RANKL induction in osteocyte, thereby aggravating post-fracture systemic bone loss. And the findings highlight that modulating the IL-6/STAT3/RANKL axis and targeting osteocyte function may offer a promising therapeutic approach for preventing bone loss and minimizing the risk of fracture recurrence.

Background: Transient receptor potential channel subfamily M member 4 (TRPM4) is a non-selective Na⁺ permeable ion channel that regulates disease processes by enhancing sodium entry and membrane depolarization, but its role in tumors remains underexplored. The purpose of this study is to investigate the role of TRPM4 in pan-cancer progression and immune regulation.

Methods: The pan-cancer mRNA expression information of TRPM4 was obtained from TCGA and GTEx, and the protein expression information of TRPM4 was obtained from HPA database. STRING database was utilized to construct the protein-protein interaction network of TRPM4. Gene characterization of TRMP4 was analyzed by GSCA database. The relationship between TRPM4 and immune infiltration characteristics in pan-cancer was analyzed using TCGAplot. Multiple bulk RNA-seq and scRNA-seq datasets treated with PD-(L)1 were used to analyze the relationship between TRPM4 and immunotherapy response. Immunohistochemistry (IHC) and multiplex immunofluorescence (mIHC) were used to validate the expression of TRPM4 in tumor tissue from 19 lung adenocarcinoma patients in relation to the characteristics of immune cell infiltration. In vitro experiments were performed to validate the role of TRPM4 in human breast, lung adenocarcinoma, and esophageal cancer.

Results: TRMP4 expression is higher in most tumors than in normal tissues, and the association with prognosis varies with cancer type. TRPM4 correlates with multiple immune checkpoints as well as the degree of immune cell infiltration. Multiple datasets of anti-PD-(L)1 treatment suggested that high expression of TRPM4 was associated with worse treatment prognosis. The IHC and mIHC found that TRPM4 expression was negatively correlated with the level of M1 macrophage and T cell infiltration. In vitro experiments confirmed that knockdown of TRPM4 inhibited proliferation, invasion and migration of human breast, lung and esophageal cancer cells.

Conclusion: TRPM4 plays a complex role in tumor progression and immunotherapeutic response, and targeting TRPM4 may offer promising strategies for inhibiting tumor progression and improving immunotherapy resistance.

Background: Hepatocellular carcinoma (HCC) frequently develops resistance to sorafenib, a first-line treatment for advanced HCC. While PD-L1 contributes to immune evasion and direct tumor survival, its role in modulating sorafenib resistance via non-immunological pathways remains unclear. This study investigates the PD-L1/ITGB4 axis in regulating sorafenib sensitivity.

Methods: Bioinformatics analysis of HCC datasets identified PD-L1/ITGB4 co-expression. Protein interaction was validated via co-immunoprecipitation (Co-IP). Functional impacts on FAK/AKT/mTOR signaling were assessed using kinase inhibitors and gene knockdown in HCC cell lines. Sorafenib sensitivity was evaluated in vitro and in xenograft models with mono- and combination therapies (PD-L1/ITGB4 inhibition ± sorafenib).

Results: PD-L1 directly interacts with ITGB4 to activate the FAK/AKT/mTOR signaling pathway, independent of its immune-regulatory functions. This interaction critically mediates sorafenib resistance in HCC, as evidenced by significantly reduced drug sensitivity in PD-L1^high/ITGB4^high cells (p < 0.001). Crucially, genetic knockdown of either PD-L1 or ITGB4 effectively reversed this chemoresistance phenotype. In translational validation, combined pharmacological inhibition of the PD-L1/ITGB4 axis with sorafenib synergistically suppressed tumor progression in vivo, achieving >60% greater volume reduction compared to monotherapies.

Conclusion: The PD-L1/ITGB4 axis drives sorafenib resistance via FAK/AKT/mTOR hyperactivation. Dual targeting of PD-L1/ITGB4 enhances sorafenib efficacy, revealing a tumor-intrinsic mechanism and proposing a novel combinatorial strategy for HCC.

Introduction: Autoimmune glial fibrillary acidic protein astrocytopathy (A-GFAP-A) is an increasingly recognized neurological disorder with significant clinical management challenges, particularly in predicting the need for intensive care unit (ICU) admission. This study aimed to develop and validate predictive models to identify A-GFAP-A patients at increased risk for ICU admission.

Methods: We retrospectively analyzed 107 patients (January 2021 - August 2024), randomly assigned to training and validation cohorts (7:3). Variable selection for model development was performed using random forest, least absolute shrinkage and selection operator (LASSO), and extreme gradient boosting (XGBoost). Logistic regression was used to construct a nomogram, and a decision tree was developed to facilitate rapid clinical decision-making. Model performance was assessed by area under the curve (AUC), calibration plots, and decision curve analysis (DCA).

Results: Four key predictors of ICU admission were identified: Glasgow Coma Scale (GCS) score at admission, seizures, maximum body temperature, and C-reactive protein (CRP) levels. The nomogram demonstrated excellent predictive accuracy with AUCs of 0.923 (95% CI, 0.858-0.987) in training cohort, 0.922 (95% CI, 0.836-1.000) in validation cohort, and 0.93 (95% CI, 0.883-0.972) in bootstrap validation. The model showed excellent calibration, and DCA confirmed its clinical utility. The decision tree identified GCS <15, seizures, and temperature >39°C as the most relevant indicators for high-risk stratification.

Discussion: This study presents the first validated nomogram and decision tree for ICU admission risk in A-GFAP-A, based on the largest reported cohort to date, providing a valuable tool for clinical decision-making and resource optimization.

Introduction: Increased metabolic activity is frequently observed in hepatocellular carcinoma (HCC). However, the impact of this increased metabolic activity on the efficacy of current treatments, such as the combination immunotherapy using atezolizumab and bevacizumab for HCC, remains unknown.

Methods: Gene expression data from mouse livers representing hepatic metabolic activity and HCC patient tumor tissues were used to identify a transcriptomic signature for high metabolic activity in HCC tumors. The hepatic metabolic signature (HMS) was used to categorize HCC patients treated with atezolizumab plus bevacizumab or sorafenib from the IMbrave150 clinical trial into high-or low-metabolic groups, using multiple statistical approaches to evaluate the clinical relevance of the signature.

Results: The study uncovered a robust association between high HMS and poor overall survival in HCC patients across multiple independent cohorts. Notably, high HMS patients in IMbrave150 did not show significant benefit of the atezolizumab-bevacizumab treatment in terms of overall survival or progression-free survival compared to sorafenib monotherapy. Conversely, low HMS patients demonstrated superior overall and progression-free survival outcomes with the combination regimen relative to sorafenib alone. Furthermore, an association between high HMS and features of hepatic stem cells and increased genomic instability was identified.

Conclusion: This study provides compelling evidence that the HMS could be a predictive biomarker to identify potential HCC patients with therapeutic benefits from combination immunotherapy with atezolizumab and bevacizumab. Leveraging such predictive metabolic biomarkers may pave the way for tailored, precision medicine strategies that maximize therapeutic responses and improve outcomes for HCC patients.

Mitophagy serves as a cytoprotective mechanism that is essential for eliminating dysfunctional or superfluous mitochondria, thereby fine-tuning mitochondrial quantity and maintaining cellular homeostasis. Recent studies underscore the critical role of mitophagy in determining the fate and function of host cells infected by Mycobacterium tuberculosis. The successful pathogen strategically integrates into the host's mitochondrial network, manipulating processes such as apoptosis, metabolic reprogramming, mitochondrial fusion and fission, and reactive oxygen species production. Therefore, understanding those mechanisms is critical for the advancements of host-directed therapies against tuberculosis. This study offers a comprehensive overview of the interplay between Mycobacterium tuberculosis and mitophagy, emphasizing the associated signaling pathways and potential therapeutic targets involved in mitophagy in Mycobacterium tuberculosis infection. Activating mitophagy in infected host cells represents a promising avenue for improving therapeutic outcomes against tuberculosis. This review aims to summarize potential research direction for agents targeting induction of mitophagy. Notably, evidence suggests that BNIP3/NIX-mediated mitophagy may serve as a potential therapeutic target.

Objective: This study aims to compare the effectiveness and safety of TACE combined with molecular targeted therapy (MTT) plus Programmed death-ligand 1 (PD-(L)1) antibodies versus MTT plus PD-(L)1 antibodies for HCC patients.

Methods: Data from HCC patients who received either MTT plus PD-(L)1 (systemic therapy group) or TACE combined with MTT plus PD-(L)1 (combination therapy group) were retrospectively analyzed. The primary outcome was the objective reaction rate (ORR) at the initial assessment post-treatment initiation. Secondary outcomes included progressive free survival (PFS), overall survival (OS) and grade-3 or higher adverse events.

Results: A total of 222 HCC patients were included (109 in the systemic therapy group, 113 in the combination therapy group). Propensity score matching yielded 80 patients per group. The odds ratio for ORR in the combination therapy group was 1.29 (95% CI: 0.64-2.60; p=0.479). Subgroup analysis revealed significantly higher ORR for patients with AFP≤200 ng/mL in the combination therapy group (OR=3.54, p=0.016). For patients without PVTT, the ORR odds were slightly higher with combination therapy (OR=5.33, p=0.068). Multivariate Cox regression analysis showed no significant differences in PFS (HR=0.68, p=0.131) or OS (HR=0.86, p=0.674) between the two groups. Higher baseline AFP (>200 ng/mL) was associated with worse PFS (HR=1.68, p=0.012) and OS (HR=2.33, p=0.021). Surgical resection improved PFS (HR=0.42, p<0.001) and OS (HR=0.31, p=0.004). Grade 3 or higher adverse events were more common in the combination therapy group (52% vs 15%, p<0.0001).

Conclusion: No significant benefits were observed for combining TACE with MTT and PD-(L)1 in unresectable HCC patients. However, TACE may offer advantages for patients with AFP≤200 ng/mL or without PVTT.

Combining external beam radiation therapy (EBRT) with immunotherapy showed promise pre-clinically by inducing immunogenic cell death (ICD) thus releasing damage-associated molecular patterns (DAMPs) and cytokines to activate the immune system. Clinical results, however, have often been disappointing. Radioligand therapy (RL), which uses targeted radionuclides to deliver cytotoxic radiation, offers advantages over EBRT by treating multiple tumors simultaneously. Combining RL with immunotherapy faces challenges, as prolonged radiation exposure can damage immune cells, and the "cross-fire" and "bystander" effects may harm incoming effector cells. Current RL therapies require multiple doses, further complicating immune cell viability. To optimize RL-immunotherapy combinations, timing is critical. Administering immunotherapy weeks after RL therapy may reduce radiation-induced immune cell damage. Additionally, selecting radionuclides with shorter half-lives could minimize immune cell toxicity while maintaining tumor-killing efficacy. Future RL therapies should prioritize radionuclides with optimal emission profiles and half-lives to enhance synergy with immunotherapy and improve clinical outcomes.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is one of the most prevalent chronic liver diseases worldwide. It is characterized by hepatic steatosis in the absence of significant alcohol consumption, and can progress to liver fibrosis, cirrhosis, and even hepatocellular carcinoma (HCC). Despite its widespread impact, treatment options remain limited, and effective therapies targeting the underlying disease mechanisms are lacking. Recent studies have highlighted the critical role of the liver's immune microenvironment in the onset and progression of MAFLD. However, research into immune-based therapies remains in its early stages. Most existing studies have focused on understanding the immune mechanisms involved, but specific immune targets and therapeutic strategies have yet to be fully explored. This gap has hindered the development of targeted immunotherapies for MAFLD. This review aims to examine the molecular mechanisms of the immune microenvironment in MAFLD and identify potential therapeutic targets, offering insights for future clinical and scientific advancements.