The activity and immune dynamics of PD-1 inhibition on high-risk pulmonary ground glass opacity lesions: insights from a single-arm, phase II trial.

Immune checkpoint inhibitors targeting the programmed cell death-1 (PD-1) protein significantly improve survival in patients with advanced non-small-cell lung cancer (NSCLC), but its impact on early-stage ground-glass opacity (GGO) lesions remains unclear. This is a single-arm, phase II trial (NCT04026841) using Simon's optimal two-stage design, of which 4 doses of sintilimab (200 mg per 3 weeks) were administrated in 36 enrolled multiple primary lung cancer (MPLC) patients with persistent high-risk (Lung-RADS category 4 or had progressed within 6 months) GGOs. The primary endpoint was objective response rate (ORR). T/B/NK-cell subpopulations, TCR-seq, cytokines, exosomal RNA, and multiplexed immunohistochemistry (mIHC) were monitored and compared between responders and non-responders. Finally, two intent-to-treat (ITT) lesions (pure-GGO or GGO-predominant) showed responses (ORR: 5.6%, 2/36), and no patients had progressive disease (PD). No grade 3-5 TRAEs occurred. The total response rate considering two ITT lesions and three non-intent-to-treat (NITT) lesions (pure-solid or solid-predominant) was 13.9% (5/36). The proportion of CD8+ T cells, the ratio of CD8+/CD4+, and the TCR clonality value were significantly higher in the peripheral blood of responders before treatment and decreased over time. Correspondingly, the mIHC analysis showed more CD8+ T cells infiltrated in responders. Besides, responders' cytokine concentrations of EGF and CTLA-4 increased during treatment. The exosomal expression of fatty acid metabolism and oxidative phosphorylation gene signatures were down-regulated among responders. Collectively, PD-1 inhibitor showed certain activity on high-risk pulmonary GGO lesions without safety concerns. Such effects were associated with specific T-cell re-distribution, EGF/CTLA-4 cytokine compensation, and regulation of metabolism pathways.

Identification of key genes and pathway related to chemoresistance of small cell lung cancer through an integrative bioinformatics analysis.

Background: Small cell lung cancer (SCLC), the most malignant of all the lung cancer subtypes, is characterized by drug resistance. This study sought to explore the key genes and pathways associated with the chemoresistance of SCLC. Methods: The drug sensitivity of chemosensitive and chemoresistance SCLC cell lines was measured by Cell Counting Kit-8 assays. The total RNA from chemosensitive cell line H69 and chemoresistance cell line H69AR cells was extracted and subjected to messenger RNA (mRNA) and long non-coding RNA (lncRNA) microarray analyses. The differentially expressed genes (DEGs) and the differentially expressed lncRNAs (DELs) were screened out with a threshold of a |log fold change | ≥1 and an adjusted P value <0.05. A protein-protein interaction network was constructed, and hub genes were screened out. A lncRNA-mRNA co-expression network was also constructed. Gene Ontology and Kyoto Encyclopedia of Genes, Genomes enrichment analyses and Cis-regulatory element analyses were conducted on the DEGs and the top 10 upregulated DEL-co-expressed DEGs. The expression of the key genes was further analyzed in the GSE149507 data set and validated in H69/H69AR and H446/H446DDP cells by quantitative polymerase chain reaction assays. Results: The microarray results showed that a total of 609 mRNAs and 394 lncRNAs were differentially expressed in the chemoresistant SCLC cells. The mammalian target of rapamycin (mTOR) signaling pathway was enriched among the DEGs, the top 10 upregulated DEL-co-expressed DEGs, and the NCRNA00173-co-expressed DEGs, which included IGF1, INS, WNT6, WNT11, WNT2B, and SESN2. IGF1, WNT2B, and SESN2 were downregulated, and WNT11 was upregulated in the SCLC tumor tissues in the GSE149507 data set. Further, IGF1, WNT6, WNT11, and WNT2B were lowlier expressed and SESN2 and NCRNA00173 were more highly expressed in the chemoresistant cells than sensitive cells. Conclusions: The top 10 upregulated DELs containing NCRNA00173 may be involved in the regulation of drug resistance in SCLC. These DELs may regulate the genes related to the mTOR signaling pathway. These genes may also be biomarkers and potential targets for the treatment of SCLC.

MiR-200 family and cancer: From a meta-analysis view.

The role of microRNAs (miRNAs) in cancer development was implicated as oncogene or tumor suppressor. One of the miRNA family, the miR-200 family, was mainly characterized as tumor suppressor. However, controversial results were reported. The associations between miR-200 family (consisting of five miRNAs: miR-141/200a/200b/200c/429) and cancer prognosis were inconsistent. Therefore, we conducted a meta-analysis by searching PubMed and Embase databases for studies assessing the association between the expression of miR-200 family and patients' survival of cancers. Hazard ratios (HRs) with 95% confidence intervals (CIs) were extracted from the studies and pooled HRs was determined to evaluate the association. This meta-analysis comprised 58 articles with 8107 cancer patients. The overall analysis showed that patients with higher expression of miR-200 family were associated with worse survival (HR = 1.206, 95% CI: 1.115-1.305, p < 0.001). In the stratified analysis, high level of miR-200b and miR-200c was associated with poor patients' survival. In the subgroup analysis, expression of miR-200a and miR-429 was associated with survival of breast cancer and liver cancer, respectively. Expression of miR-141 was found to be associated with favorable patients' survival in pancreatic cancer (HR = 0.275, 95% CI: 0.104-0.727, p = 0.009). In the subgroup analysis of sample type of miR-141, reverse associations with patients' survival were found from tissue (HR = 0.769, 95% CI: 0.597-0.990, p = 0.042) and blood (HR = 1.496, 95% CI: 1.183-1.893, p = 0.001). Our findings revealed that association between miR-200 family and prognosis of various cancer types was significant and the results needed specific interpretation.

Efficacy and safety of nimotuzumab in addition to radiotherapy and temozolomide for cerebral glioblastoma: a phase II multicenter clinical trial.

Background: Nimotuzumab is a humanized anti-epidermal growth factor receptor (EGFR) antibody that has shown preclinical and clinical anticancer activity in cerebral glioblastoma multiforme (GBM). We conducted a phase II, single-arm, multicenter clinical trial to evaluate the benefit of adding nimotuzumab to current standard chemo-radiotherapy for patients with GBM with positive EGFR expression. Methods: Newly diagnosed patients with histologically proven single supratentorial GBM and epidermal growth factor receptor (EGFR) positive expressions were recruited. All patients were treated with nimotuzumab, administered once a week intravenously for 6 weeks in addition to radiotherapy with concomitant and adjuvant temozolomide after surgery. The primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary objectives included objective response rate (ORR) and toxicity. Results: A total of 39 patients were enrolled and 36 patients were evaluated for efficacy. The ORR at the end of RT was 72.2%. Median OS and PFS were 24.5 and 11.9 months. The 1-year OS and PFS rates were 83.3% and 49.3%. The 2-year OS and PFS rates were 51.1% and 29.0%. O (6)-methylquanine DNA methyl-tranferase (MGMT) expression is known to affect the efficacy of chemotherapy and status of its expression is examined. No significant correlation between treatment outcomes and MGMT status was found. Most frequent treatment-related toxicities were mild to moderate and included constipation, anorexia, fatigue, nausea, vomiting, and leucopenia. Conclusions: Our study show that nimotuzumab in addition to standard treatment is well tolerable and has increased survival in newly diagnosed GBM patients with EGFR positive expression.

MicroRNA-379-5p inhibits tumor invasion and metastasis by targeting FAK/AKT signaling in hepatocellular carcinoma.

Some microRNAs (miRNAs) have been implicated in hepatocellular carcinoma (HCC) development and progression. However, the roles and mechanisms of several miRNAs in HCC remain poorly understood. Here, we report that miR-379-5p, which is down-regulated in HCC tissues and cell lines, is associated with advanced TNM stage and metastasis in HCC. The ectopic overexpression of miR-379-5p inhibited HCC cell migration, invasion, epithelial-to-mesenchymal transition (EMT) and metastasis both in vitro and in vivo. Conversely, miR-379 knockdown increased migration, invasion and EMT in HCC cells. Moreover, miR-379-5p exerted this function by directly targeting focal adhesion kinase (FAK) 3'-UTR and repressing FAK expression, thus leading to suppression of AKT signaling. Furthermore, the tumor suppressive effects of miR-379-5p in HCC cells were reversed by activating AKT signaling or restoring FAK expression. In clinical samples of HCC, miR-379-5p negatively correlated with FAK, which was up-regulated in HCC. Taken together, our findings highlight the important role of miR-379-5p in regulating the EMT and metastasis of HCC by targeting FAK/AKT signaling, suggesting that miR-379-5p may represent a novel potential therapeutic target and prognostic marker for HCC.

Expression of GOLPH2 is associated with the progression of and poor prognosis in gastric cancer.

Golgi phosphoprotein 2 (GOLPH2) has been associated with the development and progression of various human cancers. The aims of this study were to investigate the relationship between GOLPH2 and gastric cancer (GC) progression and explore the clinical significance of GOLPH2 in GC. GOLPH2 expression was examined in four pairs of primary GC tissues and the adjacent non-cancerous tissues from the same patients, using immunohistochemistry (IHC), quantitative PCR and western blotting. Furthermore, GOLPH2 protein expression was analyzed in 10 normal gastric tissues and 385 clinicopathologically characterized cases of GC by IHC. Statistical analyses were performed to determine the prognostic and diagnostic associations. GOLPH2 mRNA and protein expression were both markedly upregulated in GC tissues, compared with the paired adjacent non-cancerous tissues. The Chi-square test and Spearman analysis revealed a significant correlation between GOLPH2 expression and clinical stage, T classification, lymph node metastasis, metastasis and venous invasion. Patients with a higher GOLPH2 expression had a shorter overall survival (OS), compared to patients with lower GOLPH2 expression. Notably, our results suggested that GOLPH2 is associated with the development and progression of GC. Therefore, additional studies focusing on the potential of GOLPH2 as a novel therapeutic target in GC are required.

Prognostic value of soluble MICA levels in the serum of patients with advanced hepatocellular carcinoma.

Serum levels of soluble MHC class I-related chain A (sMICA) are related with the prognosis of various types of cancer; however, few studies on the prognostic value of sMICA in hepatocellular carcinoma (HCC) have been reported. In this study, we retrospectively investigated the relationship between sMICA levels and clinical features of advanced HCC, and we assessed the prognostic value of sMICA in advanced HCC. Furthermore, the relationship of serum sMICA levels and natural killer group 2, member D (NKG2D) expression on natural killer (NK) cells was also evaluated. We detected sMICA levels in the serum of 60 advanced HCC patients using enzyme-linked immunosorbent assay (ELISA) and measured expression levels of NKG2D on NK cells using flow cytometry. We found that serum sMICA levels in HCC patients were in the range of 0.10-6.21 ng/mL. Chi-square analyses showed that sMICA level was significantly related with only tumor size. Survival analysis showed that a high sMICA level was significantly related with poor prognosis among HCC patients. Multivariate analyses indicated that sMICA was an independent prognostic factor. In addition, the levels of CD56+NKG2D+ NK cells were within the range of 11.2%-55.4%, and correlation analyses indicated that sMICA level was negatively correlated with the level of NKG2D+ NK cells. Our results suggest that serum sMICA levels may be an independent prognostic factor for advanced HCC.

Decreased expression of XPO4 is associated with poor prognosis in hepatocellular carcinoma.

BACKGROUND AND AIM: Exportin 4 (XPO4) is a recently-discovered candidate tumor-suppressor gene identified in a liver cancer mouse model. To investigate the role of XPO4 in hepatocellular carcinoma (HCC) pathogenesis, we determined XPO4 expression and its correlation to prognosis in human primary HCC. METHODS: The XPO4 mRNA transcription level in HCC cell lines and tissue samples were detected by real-time quantitative polymerase chain reaction (PCR). XPO4 protein expression in 123 primary HCC clinical surgical specimens were analyzed by immunohistochemical detection. RESULTS: Real-time quantitative PCR showed a decrease in XPO4 expression in HCC cell lines BEL-7402, Hep-G2, and SK-hep1 compared to the normal liver cell line LO2. Decreased XPO4 mRNA was also found in the majority of tumor tissues compared with matched non-tumor liver tissues (P = 0.004). Immunohistochemical detection revealed that XPO4 expression was reduced in 51 of 123 (41.5%) tumor resection samples compared with adjunct non-tumor tissues. We also found XPO4 expression to be significantly correlated with tumor size (P = 0.045) and histopathological classification (P = 0.004). Kaplan-Meier survival curves showed that the downregulation of XPO4 resulted in a significantly poor prognosis (P = 0.008, log-rank test), and multivariate Cox's analysis showed that XPO4 expression was an independent prognostic factor for overall survival of HCC patients (P = 0.013). CONCLUSIONS: Our data suggest that XPO4 could be involved in the progression of human HCC and could serve as a potential target for gene therapy in the treatment of HCC.

Decreased expression of BATF2 is associated with a poor prognosis in hepatocellular carcinoma.

Human BATF2, a basic leucine zipper protein, was recently detected in several normal immortalized cell lines but not in transformed cell lines. In addition, the expression of BATF2 also slowed the growth rate of malignant tumor cells injected into athymic nude mice. In this study, to study the role of BATF2 in hepatocellular carcinoma (HCC), we examined BATF2 expression in 50 paired HCC tumorous and nontumorous tissues, as well as in five HCC cell lines. Moreover, BATF2 expression in 114 HCC patients was evaluated using immunohistochemistry, and its relationship with clinicopathological parameters and prognosis was investigated. We found that BATF2 expression was significantly reduced in most HCC tumorous tissues, when compared with nontumorous tissues, as well as in the five HCC cell lines. Consistent with these results, the immunohistochemistry revealed that decreased BATF2 expression was present in 63 of the 114 cases and was significantly correlated with age (p = 0.006), tumor size (p = 0.046) and tumor differentiation (p = 0.030). Patients with negative BATF2 expression showed a shorter survival than those with positive expression (p = 0.016). Multivariate analysis revealed that BATF2 expression was an independent predictor of overall survival (p = 0.015). All the data support the hypothesis that BATF2 plays an important role in the progression of HCC and that it may work as a candidate tumor suppressor and a prognostic marker as well as a potential target for treatment.

Comparative analysis of cytotoxic T lymphocyte response induced by dendritic cells loaded with hepatocellular carcinoma -derived RNA or cell lysate.

The choice of the tumor antigen preparation used for dendritic cell (DC) loading is important for optimizing DC vaccines. In the present study, we compared DCs pulsed with hepatocellular carcinoma (HCC) total RNA or cell lysates for their capacity to activate T cells. We showed here that HCC total RNA pulsed-DCs induced effector T lymphocyte responses which showed higher killing ability to HCC cell lines, as well as higher frequency of IFN-γ producing of CD4+ and CD8+ T cells when compared with lysate pulsed-DCs. Both of RNA and lysate loading did not influence the changes of mature DC phenotype and the capacity of inducing T cell proliferation. However, HCC lysate loading significantly inhibited the production of inflammatory cytokines IL-12p70, IFN-γ and enhanced the secretion of anti-inflammatory cytokines IL-10 of mature DCs. Our results indicated that DCs loaded with HCC RNA are superior to that loaded with lysate in priming anti-HCC CTL response, suggesting that total RNA may be a better choice for DCs-based HCC immunotherapy.

High expression level of EDIL3 in HCC predicts poor prognosis of HCC patients.

AIM: To determine the role of epidermal growth factor-like repeats and discoidin I-like domains 3 (EDIL3) in pathogenesis of hepatocellular carcinoma (HCC) by investigating the EDIL3 expression in HCC and its prognostic value for HCC. METHODS: EDIL3 expression was detected in 101 HCC surgical tissue samples with immunohistochemistry method, and its relation with clinicopathologic features and prognosis of HCC patients was analyzed. RESULTS: EDIL3 was highly expressed in 48.5% of the HCC patients. Although the EDIL3 expression level did not correlate with any clinicopathological parameters, Kaplan-Meier survival analysis showed that high expression level of EDIL3 resulted in a significantly poor prognosis of HCC patients (log-rank test, P = 0.010). Multivariate Cox's analysis showed that the EDIL3 expression level was a significant and independent prognostic parameter for the overall survival rate of HCC patients (hazard ratio = 1.978, 95% confidence interval = 1.139-3.435, P = 0.015). CONCLUSION: High expression level of EDIL3 predicts poor prognosis of HCC patients. EDIL3 may be a potential target of antiangiogenic therapy for HCC.

Extensive analysis of D7S486 in primary gastric cancer supports TESTIN as a candidate tumor suppressor gene.

BACKGROUND: High frequency of loss of heterozygosity (LOH) was found at D7S486 in primary gastric cancer (GC). And we found a high frequency of LOH region on 7q31 in primary GC from China, and identified D7S486 to be the most frequent LOH locus. This study was aimed to determine what genes were affected by the LOH and served as tumor suppressor genes (TSGs) in this region. Here, a high-throughput single nucleotide polymorphisms (SNPs) microarray fabricated in-house was used to analyze the LOH status around D7S486 on 7q31 in 75 patients with primary GC. Western blot, immunohistochemistry, and RT-PCR were used to assess the protein and mRNA expression of TESTIN (TES) in 50 and 140 primary GC samples, respectively. MTS assay was used to investigate the effect of TES overexpression on the proliferation of GC cell lines. Mutation and methylation analysis were performed to explore possible mechanisms of TES inactivation in GC. RESULTS: LOH analysis discovered five candidate genes (ST7, FOXP2, MDFIC, TES and CAV1) whose frequencies of LOH were higher than 30%. However, only TES showed the potential to be a TSG associated with GC. Among 140 pairs of GC samples, decreased TES mRNA level was found in 96 (68.6%) tumor tissues when compared with matched non-tumor tissues (p < 0.001). Also, reduced TES protein level was detected in 36 (72.0%) of all 50 tumor tissues by Western blot (p = 0.001). In addition, immunohistochemical staining result was in agreement with that of RT-PCR and Western blot. Down regulation of TES was shown to be correlated with tumor differentiation (p = 0.035) and prognosis (p = 0.035, log-rank test). Its overexpression inhibited the growth of three GC cell lines. Hypermethylation of TES promoter was a frequent event in primary GC and GC cell lines. However, no specific gene mutation was observed in the coding region of the TES gene. CONCLUSIONS: Collectively, all results support the role of TES as a TSG in gastric carcinogenesis and that TES is inactivated primarily by LOH and CpG island methylation.

Comparative study on anti-tumor immune response of autologous cytokine-induced killer (CIK) cells, dendritic cells-CIK (DC-CIK), and semi-allogeneic DC-CIK.

BACKGROUND AND OBJECTIVE: Cytokine-induced killer (CIK) cells and autologous dendritic cells-CIK (DC-CIK) cells co-cultured with autologous dendritic cells (DCs) and CIK cells are commonly used for immunotherapy recently. We compared the anti-tumor immune response of CIK cells, autologous DC-CIK cells, and semi-allogeneic DC-CIK cells to explore a more effective anti-tumor adoptive immunotherapy approach. METHODS: Peripheral monocytes were isolated from patients with renal carcinoma, lung cancer, or maxillary squamous cell carcinoma and their healthy adult children. Isolated cells were cultured and induced as DCs and CIK cells in vitro. CIK cells from patients were co-cultured with autologous DCs and DCs from their children respectively, generating DC-CIK cells and semi-allogeneic DC-CIK cells. The anti-tumor activities of autologous CIK cells, autologous DC-CIK cells, and semi-allogeneic DC-CIK cells were measured by LDH assay. Intracellular staining was used to test the secretion of cytokines. Flow cytometry was applied for detecting the phonotype changes of these three types of cells. Cell proliferation and cell apoptosis were detected by 5,6-carboxyfluorescein diacetate succinimidyl ester (CFSE) and Annexin V/PI respectively. RESULTS: Compared with autologous CIK cells and DC-CIK cells, semi-allogeneic DC-CIK cells significantly enhanced the anti-tumor activity and IFN-gamma secretion, reduced IL-4 secretion, increased the ratio of CD3(+)CD56(+) cells and CD3(+)CD8(+) cells, decreased the number of CD4(+)CD25(+) cells, promoted cell proliferation, and lessened cell apoptosis. CONCLUSIONS: Semi-allogeneic DC-CIK cells had a stronger anti-tumor effect than did autologous CIK cells and DC-CIK cells. Our results provided experimental evidence for clinical application of DC-CIK cells.

Dendritic cells-mediated CTLs targeting hepatocellular carcinoma stem cells.

Immunotherapy, especially using dendritic cells (DCs)-based vaccine, appears promising in the treatment of hepatocellular carcinoma (HCC) following surgery. However, the therapeutic efficacy of current DC vaccines loaded with HCC antigen is limited in clinical practice. One important reason might be that the DC vaccines for the treatment of HCC were not aimed at targeting the hepatocellular carcinoma cancer stem cells (HCCCSCs). Therefore, establishing an immunotherapy to kill HCC stem cells could be a novel therapeutic strategy. In this study, we have developed an immunotherapy to target CD133(+) HCC cells in the treatment of HCC. This study had three main findings; (1) CD133(+)HCC cells RNA loaded DCs could induce special CD8(+) cytotoxic T lymphocytes (CD133(+)Huh7-CTLs) response against CD133(+) Huh7 cells in vitro. (2) Huh7 cells-induced tumor growth in vivo was effectively inhibited by CD133(+)Huh7-CTLs. (3) the great inhibition potential of CD133(+)Huh7-CTLs to Huh7-induced tumor growth might not be only associated with anti-tumor cytokines such as IFNγ, but also to CD133(+)Huh7-DCs induced specific CTLs. This study shows an experimental proof that CD133(+)HCC cells RNA loaded DC vaccine has potential in treating HCC and may provide a new therapy for clinical post operative adjuvant therapy in future.

Therapeutic safety and effects of adjuvant autologous RetroNectin activated killer cell immunotherapy for patients with primary hepatocellular carcinoma after radiofrequency ablation.

Hepatocellular carcinoma (HCC) recurs frequently after minimally invasive therapy. Adoptive immunotherapy is considered helpful in lowering recurrence and metastasis rates of malignant tumors. In this study, we report the combination of radiofrequency ablation (RFA) and autologous RetroNectin activated killer (RAK) cells in the treatment of HCC patients with a tumor size less than 4 cm. Autologous RAK cells were transfused via an intravenous drip into the patients. Flow cytometry was used to assess the change of percentages of lymphocyte subsets in the peripheral blood of the patients. Computed tomography was used to observe the tumor recurrent conditions of patients by every 2 m. During a seven-month follow-up, no severe adverse events, recurrences or deaths were observed in all 7 HCC patients. These preliminary results suggest the feasability and safety of the combined therapeutic regimen for HCC, and that the RAK cell adoptive immunotherapy might be helpful in preventing recurrence in HCC patients after RFA.

Analysis of loss of heterozygosity on chromosome 4q in hepatocellular carcinoma using high-throughput SNP array.

To identify tumour suppressor genes (TSGs) associated with hepatocellular carcinoma (HCC) on chromosome 4q using a high-throughput single nucleotide polymorphism (SNP) array, we first scanned for loss of heterozygosity (LOH) of 40 SNPs on chromosome 4q and discovered 2 hot regions: 4q24-26 and 4q34.3-35. We then further scanned for LOH of 338 SNPs in genes around 4q34.3-35 and discovered 3 genes with the most frequent LOH: nei endonuclease VIII-like 3 (NEIL3), interferon regulatory factor 2 (IRF2) and inhibitor of growth family member 2 (ING2). A review of the literature indicates only ING2 might be a TSG associated with HCC.

Decreased expression of Neurensin-2 correlates with poor prognosis in hepatocellular carcinoma.

AIM: To investigate the expression of Neurensin-2 (NRSN2) in hepatocellular carcinoma (HCC) and its prognostic values in predicting survival. METHODS: The expression and prognostic significance of NRSN2 in HCC was examined by performing immunohistochemical analysis using a total of 110 HCC clinical tissue samples, and Western blotting analysis to further confirm the result. RESULTS: Decreased NRSN2 expression was shown in 70.9% cases. Loss of NRSN2 expression in HCC was significantly related to tumor size (P = 0.006). Larger tumor size was related to negative expression of NRSN2. Patients showing negative NRSN2 expression had a significantly shorter overall survival than those with positive expression (P = 0.008). Multivariate Cox regression analysis indicated that NRSN2 expression level was an independent factor of survival (P = 0.013). Western blotting analysis further confirmed decreased expression of NRSN2 in tumor tissues compared with non-tumorous tissues. CONCLUSION: Our study indicated that NRSN2 could be a tumor suppressor gene for HCC and a candidate biomarker for long-term survival in HCC.

The pivotal role of p38 and NF-kappaB signal pathways in the maturation of human monocyte-derived dendritic cells stimulated by streptococcal agent OK-432.

OK-432, a streptococcal preparation, has been shown as an effective activator to induce human monocyte-derived dendritic cells maturation. During this process, the activation of Toll-like receptor 4 plays an important role. However, the signaling pathway involved in has not been fully understood. In the present study, we investigated the underlying mechanisms, by which OK-432 induced maturation of human monocyte-derived DCs (MoDCs). We observed that exposure of immature MoDCs to OK-432 activated the p38 MAPK and NF-kappaB pathway, accompanied up-regulated the surface expression of maturation markers CD80, CD83, CD86 and HLA-DR, increased secretion of TNF-alpha, IL-12 and chemokine, IP-10. In addition, T cells stimulatory capacity was also enhanced. The maturation of MoDCs stimulated by OK-432 was inhibited by treatment with p38 pathway inhibitor, SB203580, or NF-kappaB pathway inhibitor, BAY-117082. Whereas, blocking of JNK pathway with SP600125 or ERK pathway with PD98059 did not influence OK-432-induced DCs maturation. Taken together, our data indicated that OK-432-induced DCs maturation was due, at least partly to the activation of p38 and NF-kappaB pathway.