ImmunoTargets and Therapy最新文献

Background: The generation of functionally active, stable T regulatory cells (Tregs) is a crucial target of type 1 diabetes (T1D) immunotherapy. This study investigated therapeutic intervention for T1D/Latent autoimmune diabetes in adults (LADA), wherein the diabetogenic proinflammatory Treg (intermediate) cell subset was characterized and driven to a Treg phenotype (CD4⁺CD25⁺FOXP3⁺). This involved simultaneous inhibition of the eukaryotic initiation factor 5a (eIF5a) and Notch pathways using GC7 (N1-Guanyl-1,7-diaminoheptane) and Anti-DLL4 (Delta-like-ligand-4).

Methods: Peripheral blood from patients with T1D/LADA and healthy adults (n=7 each) was used to isolate the CD4⁺CD25^- T cell population and CD4 deficient peripheral blood mononuclear cells (PBMCs). Cells were subjected to GAD65+GC7+anti-DLL4 treatment for seven days and compared with conventional anti-CD3/CD28/CD137 stimulation for conversion into the Tregs. Newly plasticized Tregs were assessed for their suppressive potential against freshly isolated autologous T responder cells. In addition, live, dead, and apoptotic cell counts were performed to evaluate the adverse effects of immunomodulatory treatment on immune cells. The data was analyzed with GraphPad Prism using 1- or 2-way ANOVA and a Student's t-test.

Results: A unique population of proinflammatory cytokines expressing intermediate Tregs (CD4⁺CD25^-IFNg⁺IL17⁺FOXP3⁺) was characterized in T1D/LADA patients and found significantly increased compared to age-matched healthy adults. Simultaneous inhibition of eIF5a and Notch pathways could induce Treg phenotype in Treg-deficient CD4⁺ T cells and CD4 deficient PBMCs from T1D/LADA patients. GAD65+GC7+anti-DLL4 treatment plasticized Tregs withstanding a proinflammatory milieu mimicking T1D/LADA, and the plasticized Tregs exhibited a stable and suppressive functional phenotype. Furthermore, GAD65+GC7+anti-DLL4 treatment had no adverse effects on immune cells.The present approach is a multipronged approach involving the inhibition of eIF5a and Notch pathways that addresses the upregulation of immune tolerance, differentiation, and proliferation of cytotoxic T cells and alleviates β-cell dysfunction. Additionally, this treatment strategy could also be leveraged to boost Treg generation following islet transplantation or as a combinational therapy along with adoptive cell transfer.

Purpose: Claudin18.2 has emerged as a promising therapeutic target due to its high expression in gastric (GC) and pancreatic cancers (PC). However, patients with advanced, unresectable, or metastatic GC or PC face poor prognoses, highlighting the urgent need for more effective Claudin18.2-targeted therapies.

Methods and results: We developed 4A7, a fully human monoclonal antibody with superior affinity and specificity for Claudin18.2, using a rigorous positive and negative screening strategy to eliminate cross-reactivity with Claudin18.1. In vitro, 4A7 demonstrated significantly enhanced binding activity, as well as robust antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), outperforming IMAB362, a clinical investigational antibody. In vivo, 4A7 exhibited remarkable tumor growth inhibition both as a monotherapy and in combination with anti-mPD-1, achieving superior efficacy compared to IMAB362. Additionally, 4A7 demonstrated a higher degree of humanization and comparable stability, supporting its translational potential.

Conclusion: 4A7 shows great promise as a next-generation therapeutic for Claudin18.2-positive cancers, offering improved efficacy and reduced immunogenicity. This study not only highlights 4A7's potential to address unmet clinical needs but also provides a foundation for future innovations in monoclonal antibody-based cancer therapy.

Background: Circulating immune cells and metabolites are linked to coronary atherosclerosis, but the specific causal relationships and the role of metabolites as mediators remain unclear.

Methods: Summary statistics from GWAS datasets on immune cells (n=3,757), circulating metabolites (n=8,299), and coronary atherosclerosis (cases n=51,589; controls n=343,079) were analyzed using bidirectional Mendelian randomization. Two-step and multivariate Mendelian randomization were employed to identify mediating metabolites, with inverse variance weighting (IVW) as the primary method.

Results: We identified nine immune cell phenotypes, including specific T-cell and monocyte populations, with significant causal links to coronary atherosclerosis. Additionally, 41 plasma metabolites across four metabolic pathways were identified, including 3-hydroxy-2-ethylpropionate and trans-2-hexenoylglycine. Mediation analysis revealed that 3-hydroxy-2-ethylpropionate mediated the effect of IgD+ CD24+ B-cells on coronary atherosclerosis (mediating effect: 0.961; 95% CI: 0.955-0.967), while trans-2-hexenoylglycine regulated IgD+ CD24+ B-cells, showing a mediation ratio of 16.7% (mediating effect: 0.983; 95% CI: 0.981-0.986).

Conclusion: Key immune cell phenotypes and plasma metabolites were linked to coronary atherosclerosis. The roles of 3-hydroxy-2-ethylpropionate and trans-2-hexenoylglycine in regulating B-cell function suggest potential therapeutic targets for prevention and treatment.

Background: Macrophages are highly plastic cells, and macrophage-derived exosomes (M-Exos) have been implicated in inflammation-related pathophysiologies, such as tissue injury and fibrosis repair. This study aimed to investigate the possible effects of M-Exos on the initiation and development of urethral fibrosis and stricture after injury, and to elucidate the underlying mechanisms.

Methods: In this study, we used time-tracking immunofluorescence staining for M1 and M2 macrophage markers to characterize sequential properties in the site of injured urethra. Next, we harvested these exosomes from different macrophages to co-culture with fibroblasts to further confirm the role of exosome-mediated M2 macrophage-fibroblast communication. Then, high-throughput micro-RNA (miRNA) sequencing was performed to detect the candidate exosomal miRNA and its target gene. Furthermore, fibroblasts were transfected with mRFP-GFP-LC3 plasmid to detect the autophagy role of SIRT1 in the urethral fibroblasts fibrogenesis.

Results: Here we found that M2-polarized macrophages triggered and dominated the fibrotic scene, purified exosomes from M2 macrophages exacerbated urethral fibroblast fibrogenesis, and the inhibition of exosome secretion abolished fibroblast fibrogenesis. Moreover, miR-34a-5p, which is highly enriched and packaged within M2-Exos, can be transferred from M2 macrophages into urethral fibroblasts, resulting in deterioration of proliferation and fibrogenesis. Mechanistically, M2-Exos miR-34a-5p could directly interact with the 3'-UTR of SIRT1, thereby suppressing SIRT1 expression in fibroblasts, leading to the blockage of autophagosome-lysosome fusion to impair urethral fibroblast autophagy flux and further exacerbate fibrogenesis. More importantly, repression of miR-34a-5p in M2-Exos mitigated-urethral strictures in rats with damaged urethra.

Conclusion: M2 macrophage-derived exosomes miR-34a-5p could aggravate the development of urethral fibrosis and stricture by blocking autophagosome-lysosome fusion in urethral fibroblasts and further accelerating fibrogenesis by directly targeting SIRT1, suggesting that M2-Exo miR-34a-5p and SIRT1 could serve as promising therapeutic targets for urethral stricture.

Purpose: This study aimed to investigate the risk of dermatomyositis among patients with psoriasis in a large population.

Patients and methods: Individuals aged ≥20 years with records in the TriNetX database from January 1, 2002 to December 31, 2022 were included. Diagnoses of psoriasis, non-psoriasis, dermatomyositis, and associated comorbidities were established using the International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) code. Patients who were diagnosed with dermatomyositis before the index date were excluded. Propensity score matching (PSM) was performed in a 1:1 ratio between the psoriasis group and non-psoriasis group. Kaplan-Meier curves were used to determine the cumulative incidence of dermatomyositis, and the Cox proportional hazard model was used to estimate the hazard ratio between the two groups.

Results: After PSM, 301018 individuals were included in the psoriasis and non-psoriasis groups, respectively. A higher risk of dermatomyositis was identified in patients with psoriasis than in those without (HR: 2.41, 95% CI: 2.01-2.89). This elevated risk was further confirmed in various subgroup analyses. Specifically, patients with PsA exhibited a higher incidence of dermatomyositis than those without PsA (HR, 1.73; 95% CI, 1.32-2.28). Patients treated with interleukin-17 inhibitors (IL-17i) showed a significantly higher risk of developing dermatomyositis compared to those naïve to biological agents (HR, 5.79; 95% CI, 1.57-21.31). In the European, Middle East, and Africa network and Asia-Pacific network, the risk of dermatomyositis in patients with psoriasis was higher than that in patients without psoriasis (HR (95% CI): 4.77 (1.40-16.10) and 2.50 (1.33-4.66), respectively).

Conclusion: This study revealed a higher risk of dermatomyositis in patients with psoriasis than in those without. The psoriatic patients with PsA or those who had received IL-17i treatment demonstrated a significantly higher risk of developing dermatomyositis.

Purpose: Kinesin family member 18A (KIF18A) is a member of the kinesin-8 family of motor proteins, involved in the progression and metastasis of various tumors. However, its role in pancreatic adenocarcinoma (PAAD) remains unclear.

Methods: To evaluate that role, RNA sequencing datasets, complemented by pertinent clinical metadata, were procured from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) repositories. The protein expression level of KIF18A in PAAD was derived from human protein atlas (HPA) database. The differences in KIF18A expression levels and prognostic related genes were identified through multivariate Cox regression and Lasso regression analysis to construct a prognostic risk model. The Tumor Mutation Burden (TMB), Microsatellite (MSI), immune landscape, mutation landscape and drug sensitivity of high- and low-expression KIF18A groups were assessed in immunotherapy cohorts and KIF18A expression cohorts. Finally, in vitro experiments were conducted to elucidate the molecular function of KIF18A in regulating the malignant behavior of PAAD.

Results: KIF18A is highly expressed in PAAD and is closely related to worse clinical stage and poor prognosis. Single cell analysis revealed that KIF18A is mainly expressed in microtubules of tumor cells and participated in mitosis and cell cycle of PAAD. Further analysis revealed that the expression of KIF18A is closely related to TMB, MSI, and immune cell infiltration. In vitro experiments confirmed that KIF18A promotes the proliferation, migration and expression of adhesion molecules in PAAD, and inhibits angiogenesis. In addition, the high expression of KIF18A is positively related to ferroptosis and m6A genes expression, and its high expression is driven by mutated KRAS and TP53.

Conclusion: This study confirmed that KIF18A can be used as a marker to predict the prognosis and immunotherapy of PAAD, and it participates in the formation of microtubules in PAAD cells and promotes the malignant behavior of PAAD.

As important innate immune cells, natural killer (NK) cells play an essential role in resisting pathogen invasion and eliminating transformed cells. However, the hypoxic microenvironment caused by disease conditions is an important physicochemical factor that impairs NK cell function. With the increasing prominence of NK cells in immunotherapy, there has been a surge of interest in developing biological means through which NK cells may overcome the inhibition caused by hypoxia in disease conditions. Although the effects of hypoxic conditions in shaping the functions of NK cells have been increasingly recognized and investigated, reviews have been scantly. A comprehensive understanding of how NK cells adapt to hypoxia can provide valuable insights into how the functional capacity of NK cells may be restored. This review focuses on the functional alterations of NK cells in response to hypoxia. It delineates the mechanisms by which NK cells adapt to hypoxia at the transcriptional, metabolic, translational levels. Furthermore, given the complexity of the hypoxic microenvironment, we also elucidated the effects of key hypoxic metabolites on NK cells. Finally, this review discusses the current clinical therapies derived from targeting hypoxic NK cells. The study of NK cell adaptation to hypoxia has yielded new insights into immunotherapy. These insights may lead to development of novel strategies to improve the treatment of infectious diseases and cancer.

Background: The blood proteome is a major source of biomarkers and therapeutic targets. We aimed to identify the causal proteins and potential targets for Graves' disease (GD) and Graves' ophthalmopathy (GO) via systematic genetic analyses.

Methods: Genome-wide association studies (GWASs) on the UK Biobank- Pharma Proteomics Project (UKB-PPP) collected 2923 Olink proteins from 54,219 participants. We conducted a proteome-wide Mendelian randomization (MR) study with cis-pQTLs to identify candidate proteins for GD and GO risk. Colocalization analysis and the Heidi test were used to examine whether the identified proteins and diseases shared the same variant. More proteins with potential causal associations were identified in Summary-data-based MR (SMR) analyses using trans-pQTLs. Then, downstream analyses were performed to detect protein interactions, gene function, cell type-specific expression and druggable information.

Results: This study genetically predicted levels of 62 plasma proteins were associated with GD risk. Four proteins (CD40, TINAGL1, GMPR and CXCL10) were prioritized with the evidence of sharing the same variants with GD. Specifically, some proteins had potential associations with GD with trans-pQTLs mapping in CD40. The four prioritized protein-coding genes were mainly enriched in the regulation of apoptotic and death processes. In addition, GMPR was associated with both GO and GD in a consistent direction. BTN1A1 and FCRL1 were prioritized as the causal proteins for GO onset and were not associated with GD.

Conclusion: By synthesizing proteomic and genetic data, we identified several protein biomarkers for GD, with one linked to both GD and GO and two other protein biomarkers specific to GO onset, which provides valuable insights into the etiology and potential therapeutic targets for the two diseases.

Purpose: Colorectal cancer (CRC) is a prevalent malignancy, and lactate metabolism significantly influences tumorigenesis and progression. This study identifies key genes associated with lactic acid metabolism and explore their impact on CRC.

Patients and methods: This study utilized data from The Cancer Genome Atlas, Gene Expression Omnibus, other public databases, and our institutional resources. Machine learning identified key lactate metabolism-related genes. Receiver Operating Characteristic analysis, Kaplan-Meier analysis, and the construction of a nomogram model were conducted to assess the diagnostic and prognostic significance of the key lactate metabolism-related gene EARS2. EARS2 expression in colorectal tissue was validated using both publicly available external data and samples from our institution. To investigate the mechanisms underlying EARS2 in CRC, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, Gene Set Enrichment Analysis, and Protein-Protein Interaction analyses were performed, alongside the construction of miRNA-mRNA interaction networks. Additionally, the relationships between EARS2 and immune cell infiltration, as well as responses to drug therapy, were examined. Following the knockdown of EARS2, we assessed cell proliferation, migration capabilities, and apoptosis. Statistical analyses were conducted using R and GraphPad Prism software.

Results: ERAS2 was overexpressed in CRC tissues compared to normal and adenoma tissues, with higher expression levels correlating with aberrant lactate metabolism and poorer patient prognosis. EARS2 was involved in pathways such as neuroactive ligand-receptor interactions, protein digestion, and cholesterol metabolism, and it was associated with immune cell infiltration and responses to drug treatment. Additionally, the knockdown of EARS2 inhibited the proliferation, migration, and invasion of CRC cells while enhancing their apoptosis.

Conclusion: Elevated expression of EARS2 is associated with abnormal lactate metabolism, immune cell infiltration, altered therapeutic sensitivity, and poorer survival outcomes in CRC. This correlation suggests that EARS2 may serve as a potential target for the diagnosis, prognosis, and therapeutic intervention in CRC.

Purpose: To compare the clinical outcomes of different systemic therapies, specifically PD(L)1 inhibitors plus Lenvatinib versus Atezolizumab plus Bevacizumab, when combined with hepatic arterial infusion chemotherapy (HAIC) based on the FOLFOX regimen (oxaliplatin, fluorouracil, and leucovorin) as first line treatment for unresectable hepatocellular carcinoma.

Patients and methods: This real-world retrospective study enrolled 294 patients with unresectable HCC. All patients received HAIC in combination with either PD(L)1 inhibitors plus Lenvatinib (PLEN-HAIC) or Atezolizumab plus Bevacizumab (AT-HAIC). Propensity score matching (PSM) was performed to balance patient characteristics. The overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared.

Results: After PSM, 80 and 130 patients received AT-HAIC and PLEN-HAIC, respectively. No significant differences were found in ORR between the AT-HAIC and PLEN-HAIC groups (50.0% vs 40.0% per RECIST, p = 0.202; 60.0% vs 57.7% per mRECIST, p = 0.853). Both groups showed similar disease control rates. Median PFS was 14.3 months for PLEN-HAIC versus 8.8 months for AT-HAIC (p = 0.018). Median OS was significantly better in the PLEN-HAIC group (p = 0.045, both not reached). Subgroup analysis revealed that Lenvatinib showed a better OS compared to Bevacizumab when combined with HAIC and PDL1 inhibitors (p = 0.023).

Conclusion: PLEN-HAIC offers significant survival benefits over AT-HAIC in advanced HCC. Given its remarkable efficacy, PLEN-HAIC could be a promising first-line option for unresectable HCC.