ImmunoTargets and Therapy最新文献

Purpose: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Progressive loss of motor neuron function and disruption of the blood-brain barrier are key features of ALS. Under the influence of chemokines, peripheral immune cells migrate into the central nervous system, thereby affecting the neuronal microenvironment. The aim of this study is to classify ALS based on the immune characteristics of peripheral blood in patients with the disease, and to construct prognostic models.

Patients and methods: A total of 397 ALS patients and 645 healthy controls (GSE112676 and GSE112680) were included. ALS chemotactic subtypes were constructed based on differentially expressed genes of chemokine and chemokine receptors (CCRs). The Cibersort algorithm was used to investigate the abundance of immune cells in peripheral blood. Univariate Cox regression analysis was performed to screen for CCRs genes, clinical characteristics, and immune cells associated with prognosis. Prognostic models were constructed based on these variables. Finally, external validation was conducted using samples from ALS patients diagnosed at the First Affiliated Hospital of Sun Yat-sen University.

Results: There were significant differences in the abundance of peripheral immune cells between ALS patients and healthy controls. 17 CCRs genes were identified as differentially expressed. CCL23, CCR8, CXCR4, site of onset, age of onset, and "CD4 naive T cells" were demonstrated to be significantly correlated with survival time. Two chemotactic subtypes were established. Eight prognostic models could distinguish between high-risk and low-risk ALS patients. At year five, the areas under the receiver operating characteristic curves for the PlsRcox, Coxboost, and Xgboost algorithms were 0.747, 0.733, and 0.728, respectively. External test sets successfully validated these results.

Conclusion: ALS patients exhibit peripheral immune abnormalities. Peripheral immune status could be used to distinguish ALS subtypes and construct prognostic models. Understanding peripheral immune changes in ALS patients may inform potential immunotherapies.

Background: The clinical significance and mechanistic role of immune checkpoints (ICs) in B-cell lymphoma remain underexplored. This study investigates peripheral IC expression as prognostic biomarkers and their interaction with Tregs and IL-10.

Methods: Peripheral blood from 140 B-cell lymphoma patients was analyzed using flow cytometry (PD-1, CTLA-4, LAG-3, TIM-3 on CD4⁺/CD8⁺ T cells) and ELISA. Comparisons were made across disease aggressiveness, extranodal involvement, and treatment response (complete remission [CR] vs relapse/progression [R/P]).

Results: Aggressive lymphomas and cases with multiple extranodal sites showed significantly elevated IC expression (all p < 0.05). R/P patients demonstrated markedly higher PD-1 expression (CD4⁺: 26.1% vs 8.2%; CD8⁺: 25.2% vs 7.1%; p < 0.001) and elevated CTLA-4, LAG-3, TIM-3 versus CR patients. PD-1 and CTLA-4 showed significant prognostic value (AUC > 0.7), unlike LAG-3/TIM-3. R/P patients had increased Treg proportions (7.84% vs 3.58%, P<0.0001) and IL-10 levels (10.5 vs 5.44 pg/mL, p < 0.0001). PD-1 on CD4⁺ T cells correlated positively with Treg frequency (r = 0.539, p < 0.0001) and IL-10 levels (r = 0.457, p < 0.0001).

Conclusion: Peripheral T-cell ICs, particularly PD-1 and CTLA-4, are significant prognostic biomarkers in B-cell lymphoma. The correlation between PD-1⁺ CD4⁺ T cells, Treg expansion, and IL-10 elevation is consistent with a mechanism whereby PD-1 signaling may contribute to immunosuppression through Treg differentiation and JAK2/STAT3 pathway activation, providing insights for therapeutic targeting.

In 2011, the Nobel Prize was awarded for the discovery of Toll-like receptors (TLRs) and their critical role in immunity. TLR9 is a key pattern recognition receptor that detects unmethylated cytosine-phosphate-guanine (CpG) DNA motifs, triggering innate and adaptive immune responses against pathogens and damaged host cells. Upon activation, TLR9 triggers signaling cascades that drive NF-κB, STAT3, and MAPK pathways, modulating inflammatory responses, cellular survival mechanisms, and immune regulation. While TLR9 activation is essential for immune defense, TLR9 acts as a double-dealing TLR in multiple pathologies, including cancer, autoimmunity, and chronic inflammatory disease. In cancer biology, TLR9 exhibits context-dependent roles, acting as a driver of tumorigenesis, a suppressor of tumor growth, and a regulator of immune responses, depending on the tumor type, signaling pathway, and microenvironment. It promotes tumorigenesis in leukemias, gliomas, and cancers of the prostate, bone, lung, and gastrointestinal tract, yet displays tumor-suppressive effects in triple-negative breast cancer, renal cell carcinoma, and virally-associated malignancies, through a variety of mechanisms. Clinically, synthetic CpG oligodeoxynucleotides (ODNs), which function as TLR9 agonists, have emerged as a promising approach in cancer immunotherapy, particularly in combination with other potent anticancer therapies. However, the dual nature of TLR9 signaling poses challenges for therapeutic applications. Its context-dependent effects contribute to inconsistent clinical outcomes and raise concerns about safety and toxicity. This review examines the immunologic function and signaling mechanisms of TLR9, with a focus on its complex, context-specific, and "double-dealing" roles in cancer pathogenesis and therapy.

Asthma represents a profoundly heterogeneous syndrome underpinned by multiple, distinct and overlapping immunopathological mechanisms. Nevertheless, prevailing management algorithms continue to adopt a largely uniform, stepwise approach in which pharmacotherapy is intensified only after clinical deterioration or recurrent exacerbations. Although the advent of targeted biologic agents has improved outcomes in severe asthma, the realisation of precision medicine - therapeutic selection directed by individual disease mechanisms - remains elusive. This is primarily attributable to the limited availability of validated biomarkers capable of defining endotypes and accurately predicting therapeutic responsiveness. Existing indicators of type-2 (T2) inflammation, including blood eosinophil counts, fractional exhaled nitric oxide, and serum Immunoglobulin E, provide only partial discrimination between T2 subtypes and are insufficient to guide the choice of specific T2-targeted biologics. Furthermore, robust non-T2 biomarkers are notably lacking. This review provides a critical appraisal of current biomarker paradigms and examines emerging molecular and cellular candidates with potential to enable precise endotyping. Integration of such biomarkers into early disease assessment offers the prospect of delivering truly individualised therapy, ensuring that appropriate treatment is instituted for the right patient at the optimal time.

Background: Acute kidney injury (AKI) involves complex inflammatory responses in which macrophage dysfunction plays a central role. Although histone acetyltransferase KAT2A has been implicated in immune regulation, its role in macrophage ferritinophagy during AKI remains unclear.

Methods: Single-cell RNA sequencing analysis of mouse kidney tissue identified abnormal activation of ferritinophagy and upregulation of KAT2A in renal macrophage during AKI progression. Colocalization of FTH1 and LAMP1 and the increased fluorescence intensity of FTH1 and NCOA4 proteins, and KAT2A proteins in macrophage of kidney in AKI samples were detected via immunofluorescence staining. Functional impacts of KAT2A on macrophage ferritinophagy were assessed using KAT2A knockdown and overexpression plasmids in RAW264.7 cell lines. Butyrolactone 3 (MB-3), a specific KAT2A inhibitor, was administered via intraperitoneal injection 24 hours post-IR to assess the influence of MB-3 on renal pathological changes and the activity of macrophage ferritinophagy.

Results: In this study, using single-cell RNA sequencing and dual immunofluorescence, we observed aberrant ferritinophagy in renal macrophages, marked by increased colocalization of FTH1 with LAMP1 and NCOA4, alongside elevated CD68 expression. KAT2A was upregulated in macrophages from both human AKI biopsies and murine models. Genetic knockdown of KAT2A suppressed ferritinophagy, reduced NCOA4 and FTH1 expression, decreased FTH1-LAMP1 colocalization, and inhibited cGAS signaling. Conversely, KAT2A overexpression exacerbated these processes. Critically, NCOA4 silencing abolished KAT2A-driven ferritinophagy and cGAS-STING activation. Pharmacological inhibition of KAT2A with MB-3 significantly attenuated renal injury, macrophage infiltration, and ferritinophagy, and reduced colocalization of KAT2A or NCOA4 with F4/80.

Conclusion: These findings demonstrate that KAT2A promotes AKI progression via NCOA4-mediated ferritinophagy and cGAS-STING inflammatory signaling in macrophages, highlighting KAT2A inhibition as a promising therapeutic strategy for AKI.

The introduction of immune checkpoint inhibitors (ICIs) in the treatment of cancer has significantly improved patient outcomes. Whereas ICIs have a substantially more beneficial risk profile than chemotherapy, immune-related adverse events (irAEs) are currently among the most pressing challenges of clinical oncology. It has been well established that certain variants of HLA genes are associated with increased susceptibility or a decreased risk of certain autoimmune diseases. Considering that irAEs often resemble autoimmune disorders observed in the general population, we conducted the first review summarizing the current knowledge on the link between the HLA system and the development of irAEs during ICIs treatment. We performed a comprehensive search of the US National Library of Medicine (PubMed) database. Based on the research conducted so far, our analysis indicates that certain HLA variants have been described to increase or, conversely, decrease the risk of irAEs. Thus, HLA genotyping may be useful in stratifying the risk of irAEs, allowing for more thorough screening of patients with a higher likelihood of developing ICI-related toxicities and less frequent monitoring of those at lower risk, thereby significantly reducing costs and the overall burden of disease. HLA genotyping may ultimately contribute to the personalization of cancer therapy, significantly improving patient safety and clinical efficacy. Furthermore, identifying an association between certain HLA variants and irAEs may lead to a better understanding of the pathogenesis underlying these adverse effects. Nevertheless, the studies conducted so far have included limited cohorts of patients with a wide variety of malignancies and diverse treatment regimens. Hence, further research that addresses these limitations is needed.

Background: Hepatocellular carcinoma (HCC) exhibits pronounced spatial heterogeneity that limits therapeutic efficacy. The contribution of epithelial-mesenchymal transition (EMT) to regional tumor progression and immune evasion remains incompletely understood.

Methods: We integrated bulk transcriptomic datasets (TCGA, GSE14520), 34 single-cell RNA-seq samples, and 15 spatial transcriptomic datasets to delineate EMT activity across distinct HCC regions. Immune infiltration profiling, pathway enrichment, and multi-model machine learning were used to identify candidate EMT regulators. Functional validation was performed in Hep3B cells through wound healing, Transwell migration/invasion, and immunofluorescence assays.

Results: EMT activity was significantly elevated at tumor margins (fold change = 2.7, p < 0.001) and was associated with poorer overall survival (HR = 2.15, 95% CI: 1.41-3.27, p < 0.001). Regions with high EMT signatures showed reduced CD8⁺ T-cell infiltration and increased immunosuppressive cells, including MDSCs, M2 macrophages, and Tregs, along with elevated expression of immune checkpoints (PDCD1, CTLA4, LAG3). Among candidate regulators, UBC was consistently ranked as a top EMT-associated gene across all models. Functional assays confirmed that UBC overexpression enhanced migration, invasion, and vimentin expression, whereas UBC knockdown reversed these effects.

Conclusion: Through integrative spatial multi-omics and experimental validation, we identify UBC as a key mediator of EMT and immune suppression at HCC margins. These findings provide mechanistic insight into spatial heterogeneity and suggest that targeting UBC could have translational potential for overcoming immune evasion in HCC.

Purpose: As a novel candidate in cancer immunotherapy, siglec-15-targeting antibodies hold promise for providing alternative therapeutic strategies to tumors unresponsive to programmed death ligand 1 (PD-L1) antibody therapy. To date, pharmacological development targeting siglec-15 has not yet achieved significant breakthroughs or clinical approval. Therefore, this study aims to develop a novel anti-siglec-15 antibody designed to restore tumor immune normalization.

Methods: In this study, we constructed a phage immune library derived from lymphoid tissues of lung cancer patients using phage display technology and screened the fully human antibodies against siglec-15 antigen from this library. The antibody affinity was detected by Bio-Layer Interferometry, the binding rate of antibody to positively expressing siglec-15 tumor cells was examined by flow cytometry, and the activity of antibody-mediated killer cells against tumor cells was reflected by Antibody-Dependent Cellular Cytotoxicity (ADCC) action. The blockage of proliferation inhibition caused by siglec-15 antigen by antibodies was investigated by t-lymphocyte proliferation assays, and CD8⁺ T cells were collected from malignant pleural effusion specimens derived from lung cancer patients to determinewhether antibodies could alleviate the immunosuppression present in the tumor microenvironment (TME). The anti-tumor efficacy of the antibody was investigated in vivo by constructing a zebrafish tumor model and a humanized mouse tumor model.

Results: The antibody demonstrated nanomolar affinity and specificity, enhanced antibody-dependent cellular cytotoxicity (ADCC) against tumor cells, reversed T-cell suppression, and reduced CD8⁺ T-cell exhaustion in vitro analyses. In vivo models confirmed tumor growth inhibition via increased lymphocyte infiltration and activation.

Conclusion: Antibody immune libraries from lymphoid tissues of lung cancer patients can screen specific antibodies against siglec-15 target antigens and exert certain biological functions in vitro and in vivo.

Combining radiotherapy (RT) with immune checkpoint inhibitors (ICIs) improves survival in stage III non-small cell lung cancer (NSCLC), though immune-related adverse events (irAEs) require vigilant management. Emerging evidence suggests multi-organ irAEs may correlate with favorable outcomes. We report a case of unresectable stage IIIA NSCLC achieving sustained partial response (PR) with progression-free survival (PFS) exceeding 42 months after one cycle of pembrolizumab-chemotherapy followed by sequential thoracic RT (50 Gy/25 fractions). Severe multi-organ irAEs (muscular, cardiovascular, respiratory, hematologic) developed but were effectively managed with corticosteroid-based therapy. Remarkably, durable tumor control persisted despite suboptimal therapeutic dosing and early systemic treatment discontinuation. This case demonstrates that RT-ICI synergy can induce robust systemic antitumor immunity even with dose-reduced RT, while severe multi-system irAEs may signal favorable prognosis. These findings support optimizing RT parameters (eg, dose de-escalation, target volume refinement) as a viable approach in the immunotherapy era.

Background: Tumor-associated macrophages (TAMs) play a pivotal role in facilitating tumor immune escape in colorectal cancer (CRC). C-type lectin Dendritic Cell-Specific ICAM-Grabbing Nonintegrin (DC-SIGN) is variably expressed in TAMs in tumor tissues. However, its role in CRC progression remains poorly defined.

Methods: We analyzed The Cancer Genome Atlas (TCGA) data and an independent CRC cohort to evaluate the prognostic significance of DC-SIGN^high TAMs. Immunofluorescence and flow cytometry were used to characterize DC-SIGN expression in CRC tissues. RNA sequencing and bioinformatics analyses were performed on sorted DC-SIGN^high and DC-SIGN^low TAMs. Functional assays using THP-1-derived macrophages and primary TAMs were conducted to examine how DC-SIGN regulates PD-L1 expression via the transcription factor BCL-3.

Results: DC-SIGN was specifically expressed in TAMs within CRC tissues and was associated with increased stromal and immune cell infiltration. DC-SIGN expression correlated with worsened prognosis in CD8^high, but not CD8^low, patients with CRC across two independent cohorts, and served as an independent predictor of unfavorable survival in CD8^high CRC. Transcriptomic profiling revealed that DC-SIGN^high TAMs exhibited distinct immune-related pathways, including marked upregulation of PD-L1 and PD-L1 immune checkpoint pathway. Mechanistically, Lewis^x-ligated DC-SIGN upregulated PD-L1 expression at both mRNA and protein levels through BCL-3, which directly bound to the PD-L1 promoter.

Conclusion: The DC-SIGN/BCL-3 axis in TAMs drives PD-L1 expression and contributes to CRC immune evasion. Targeting DC-SIGN⁺ TAMs may represent a promising therapeutic strategy to reprogram the tumor microenvironment (TME) and improve the efficacy of immunotherapy in CRC.