Immunobiology最新文献

Tumor immunotherapy, particularly immune checkpoint inhibitors (ICIs), has emerged as a powerful strategy in treating malignant tumors, exhibiting efficacy in both first-line and second-line treatments for advanced non-small cell lung cancer (NSCLC). Despite their success, ICIs can lead to adverse reactions, including interstitial lung disease (ILD), with an incidence ranging from 2.7 % to 20.0 %. The lack of clear correlations with dosage, duration, or drug efficacy, coupled with nonspecific clinical manifestations, poses challenges in timely diagnosis and effective management. This study examined the association between ICIs-related ILD and serum levels of KL-6 and inflammatory markers in NSCLC patients. A total of 382 NSCLC patients with squamous cell carcinoma (SQC, n = 81), adenocarcinoma (ACA, n = 132), and large cell carcinoma (LCC, n = 169) were included, of whom 191 developed ILD following ICIs treatment. Serum KL-6, TNF-α, IL-8, and IL-6 were quantified using ELISA. Results showed significantly elevated serum KL-6 levels in ILD patients (759.35 ± 214.14 U/mL) compared to those without ILD (270.81 ± 124.98 U/mL). Cancer subtype analysis revealed increased KL-6 levels across SQC, ACA, and LCC ILD patients (SQC: 645.89 ± 255.07, ACA: 797.39 ± 192.30, LCC: 783.57 ± 191.21; p < 0.001). ROC analysis identified diagnostic thresholds for KL-6: 277.4 U/mL for SQC (sensitivity 0.9756, specificity 0.8250), 346.9 U/mL for ACA (sensitivity 0.9583, specificity 0.8333), and 281.3 U/mL for LCC (sensitivity 0.9873, specificity 0.6111). Correlation analysis showed a significant relationship between KL-6 and TNF-α (r = 0.4626, p = 0.0023), IL-8 (r = 0.5584, p = 0.0001), and IL-6 (r = 0.5336, p = 0.0003) in SQC ILD patients. These findings suggest that elevated KL-6 levels and inflammatory markers are indicative of ILD in ICIs-treated NSCLC patients, with potential diagnostic implications across cancer subtypes.

Background: Gastric cancer (GC) remains a serious health concern and is characterized by a multifactorial etiology involving both genetic and epigenetic factors. The aim of the current study was to examine the relationship between Human leukocyte antigen (HLA)-G 3'UTR polymorphisms and the expression of HLA-G in both tumor tissues and plasma samples from patients with GC in the Tunisian population.

Methods: HLA-G 3'UTR polymorphisms (14pb Insertion/deletion and + 3142C/G) were identified by polymerase chain reaction (PCR) or Sanger sequencing. Plasma levels of sHLA-G (total sHLA-G, shed HLA-G1 and HLA-G5) were determined. Immunohistochemistry was used to evaluate the expression of HLA-G in tumor tissues.

Results: The Del/Del genotype and Del allele frequencies were different between GC patients and healthy donors (HD) (OR [95 % CI] = 2.483 [1.070-5.410], p = 0.025 vs. OR [95 % CI] = 1.537 [0.924-2.584], p = 0.099; respectively). The C/C genotype and C allele frequencies were significantly greater in GC patients than in HD (OR [95 % CI] = 2.269[0.1.070-4.904], p = 0.033 vs. OR [95 % CI] = 1.746[1.045-2.878], p = 0.034; respectively). Interestingly, the Del/Del genotype and Del allele were significantly associated with an increased risk of GC in patients aged ≥55 years at diagnosis. HLA-G was highly expressed in GC tissues, particularly in tissues with advanced tumor invasion (T3 + T4). Compared with HD, GC patients had higher soluble HLA-G, shed HLA-G1 and HLA-G5 levels (Mann-Whitney: p = 0.001, p = 0.001 and p = 0.643, respectively). Assessment of patients' survival by Kaplan-Meier analysis indicated that the Del allele was significantly associated with reduced overall survival (OS) in GC patients at advanced stages III + IV (p = 0.043).

Conclusions: These results suggest that HLA-G 3'UTR polymorphisms are associated with GC susceptibility in Tunisian population. The expression of HLA-G in both the tissue and plasma may play an important role in the development and progression of GC. Therefore, the current study supported the recommendation of investigating HLA-G 3'UTR polymorphisms in GC and indicated that HLA-G molecules could serve as promising therapeutic targets in GC.

Background: A key factor underlying the failure of Chimeric Antigen Receptor-T Cell (CAR-T) therapy in ovarian cancer (OC) is the presence of an immunosuppressive tumor microenvironment, which is intricately linked to M2 polarization among tumor-infiltrating macrophages. P2X7 receptor has been previously documented as expressed within these macrophages and its correlation with M2 polarization is evident. This investigation scrutinizes whether silencing of P2X7 receptor within macrophages could lead to augmented anti-tumor potency of CAR-T.

Method: Human peripheral blood mononuclear cells were artificially differentiated into macrophages or M2 macrophage in vitro. After silencing P2X7 receptor and/or overexpressing STAT6 within macrophages, the M1 and M2 markers were evaluated via flow cytometry, ELISA, and qRT-PCR. Additionally, the phosphorylation level of STAT6 was monitored by western blot. We engineered CAR-T cells targeting the non-functional P2X7 (nfP2X7) receptor, and co-cultured them with macrophages silencing P2X7 receptor along with OC cells. The anti-tumor effect of these CAR-T cells was assessed through evaluating OC cell viability, lactate dehydrogenase release, and IFN-γ levels.

Result: P2X7 receptor silencing promotes M1 macrophage marker expression (CD86, TNF-α, IL-6, IL-1β), diminishes M2 macrophage marker expression (CD206 and IL-10) and suppresses STAT6 phosphorylation, whereas STAT6 overexpression reverses these phenomena. Furthermore, M2 macrophage suppresses the toxic effect of CAR-T cells on OC cells, while silencing the P2X7 receptor nullifies the immunosuppressive effect of M2 macrophages on CAR-T cells.

Conclusion: Silencing P2X7 receptor can reverse M2 macrophage polarization by suppressing STAT6 activation, thereby enhancing the anti-tumor efficacy of CAR-T cells targeting nfP2X7 receptor in OC cell lines.

Sepsis-associated acute kidney injury (S-AKI) is a prevalent and life-threatening complication in hospitalized and critically ill patients. Recent researches indicates that immunoproteasome, especially proteasome 20S subunit beta 8 (PSMB8), is highly associated with various kidney diseases. This study aims to investigate the potential involvement of PSMB8 in S-AKI and its impact on apoptosis and inflammation. The model of S-AKI induced by LPS (10 mg/kg) was assessed by histological examination. ELISA and Real-time PCR were used to detect the levels of inflammatory cytokines in the renal cortex. The role of shPSMB8 in LPS-induced apoptosis was detected by flow cytometry. Finally, western blot was performed to assess the NF-κB signaling pathway related proteins, and the nuclear translocation of NF-kB P65 was detected by immunofluorescence microscopy. PSMB8 knockdown substantially protected against renal injury by reducing blood urea nitrogen and creatinine levels and ameliorating inflammation. PSMB8 knockdown inhibited renal expression of interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α) and COX-2 to improve inflammatory response. Mechanistic studies demonstrated that downregulation of PSMB8 blocked LPS-induced S-AKI phosphorylation and nuclear translocation of NF-κB P65. Collectively, our results suggest that inhibition of PSMB8 significantly contributes to S-AKI via regulation of NF-κB. These findings reveal the pathogenic role of PSMB8 in AKI and suggest a novel therapeutic target for the condition.

Macrophages play a pivotal role in regulating inflammatory response in periodontitis, a condition characterized by excessive osteoclast differentiation. This study aimed to investigate whether exosomes derived from M2 macrophages regulate osteoclast differentiation and to identify the underlying molecular mechanisms. Exosomes were isolated from M2 macrophages and used to treat osteoclasts. Osteoclastogenesis was assessed using tartrate-resistant acid phosphatase staining and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The molecular mechanism was evaluated using microarray analysis, RT-qPCR, dual-luciferase reporter analysis, and RNA pull-down assay. The results showed that exosomes from M2 macrophages inhibited receptor activator of nuclear factor κ-B ligand (RANKL)-induced osteoclast differentiation. Additionally, miR-1227-5p expression in osteoclasts was increased after treatment with exosomes, and inhibition of miR-1227-5p counteracted the suppressive effects of exosomes on osteoclastogenesis. Moreover, OSCAR is a target of miR-1227-5p. In conclusion, exosomal miR-1227-5p suppresses osteoclast differentiation, potentially via targeting OSCAR. These findings provide new insights into the pathogenesis of periodontitis.

Background & aims: HBV-related acute-on-chronic liver failure (HBV-ACLF) is a severe acute liver injury secondary to HBV-related chronic liver disease (with or without cirrhosis) and is characterized by a high short-term mortality rate. Presently, there is a paucity of experimental models that specifically focus on HBV-ACLF based on chronic hepatitis B. Therefore, this study aimed to establish an experimental mouse model of HBV-ACLF using chronic hepatitis B (CHB) as a basis and investigate the impact of STING activation on the disease.

Methods: To simulate HBV-ACLF conditions, a model was constructed by combining chronic HBV replication (caudal vein high-pressure hydrodynamic injection of pAAV/HBV1.2 plasmid) and acute hepatic insult (intraperitoneal injection of Acetaminophen (APAP)). Then, model mice were administered either a STING agonist or STING inhibitor. Liver injury, STING pathway, autophagy flux, and macrophage polarization were assessed to elucidate the potential role of STING.

Results: The mouse model developed chronic hepatitis B and acute liver injury, partially reflecting features of clinical HBV-ACLF based on CHB. STING activation, autophagy, and macrophage polarization were found to be involved in the disease process. During the early stage (6 h) of the STING agonist treatment group, the STING pathway was activated, autophagy flux was up-regulated, and liver inflammation and injury were alleviated. Contrastingly, at the late stage of STING agonist treatment (24 h, 48 h), macrophages were polarized to the M1 phenotype, exacerbating liver inflammatory infiltration and injury. However, treatment with a STING covalent inhibitor reversed these effects.

Conclusions: Sting-induced autophagy exerts a protective effect on liver injury during the early stage. However, in later stages, STING may aggravate liver injury by shifting liver macrophage polarization to the M1 phenotype, thereby enhancing the inflammatory response.

Sepsis-induced myocardial injury has become a major threat to patient health and safety. Intestinal microbiota imbalance plays a crucial role in sepsis regulation. Using 16srRNA technology, we explored how intestinal colonization of Clostridium butyricum over 28 days impacted mice with LPS-induced sepsis. Significant changes were noted in the gut microbiota of the mice, highlighting that C. butyricum can positively influence the immune state in septic myocardial injury models. The bacterium's ability to prevent intestinal mucosal damage and alleviate the immunosuppressive state during the later stages of sepsis by regulating CD4 + CD25 + FOXP3 + Treg cells is particularly noteworthy. This suggests a therapeutic role for C. butyricum in sepsis management by protecting against myocardial injury and improving immune regulation.