Yonghua Wang

Qingdao University, Tsingtao, Shandong Sheng, China

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Publications (6)15.38 Total impact

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    ABSTRACT: Background: In the present study, we aimed to investigate the influence of lactate shuttling on the functional polarization and spatial distribution of transitional cell carcinoma of the bladder (TCCB) cells and macrophages. Methods: We designed a microfluidic coculture chip for real-time integrative assays. The effect of lactate shuttling on the re-education of macrophages by TCCB cells was explored by measuring the levels of NO using a total NO assay kit and by evaluating the protein expression of iNOS, p-NFkB-p65, Arg-1 and HIF-1α via cell immunofluorescence and western blotting. Additionally, we examined TCCB cell viability using acridine orange/ethidium bromide (AO/EB) and MitoTracker staining. Moreover, the concentration distributions of lactate and large signaling proteins in the culture chambers were measured using 4',6-diamidino-2-phenylindole (DAPI) and fluorescein isothiocyanate-dextran (FITC-dextran). Furthermore, the recruitment of macrophages and the influence of macrophages on BC metastasis were observed via light microscopy. Results: We confirmed that TCCB cells reprogrammed macrophages into an M2 phenotype. Moreover, lactate inhibited M1 polarization and induced M2 polarization of macrophages, but blockade of cancer cell-macrophage lactate flux significantly inhibited the re-education of macrophages by TCCB cells. In addition, lactate diffused faster and deeper than large signaling proteins in the microfluidic tumor microenvironment. Furthermore, lactate alone induced the migration of macrophages, and M1, but not M2, macrophages reduced the motility of TCCB cells. Conclusions: TCCB cells reprogrammed macrophages into an M2 phenotype in a manner that depended on cancer cell-TAM lactate flux. Furthermore, the lactate shuttle may be a determinant of the density of TAMs in tumor tissue.
    Oncotarget 10/2015; DOI:10.18632/oncotarget.5538 · 6.36 Impact Factor
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    ABSTRACT: BackgroundT cell immunoglobulin mucin-3 (Tim-3) was initially recognized as a pivotal immune checkpoint inhibitor that maintains immune homeostasis and tolerance. Recently, Tim-3 has been demonstrated to play an important role in tumor-associated immune suppression and aberrant Tim-3 expression has been reported in several human malignancies. However, the role of Tim-3 in bladder urothelial carcinoma (BUC) remains largely unknown. The present study aims to investigate Tim-3 expression in BUC and analyze correlations with clinicopathologic outcomes and postoperative survival.Methods Tim-3 protein expressions were detected in paraffin embedded sections from 100 patients with BUC by immunohistochemistry. Expressions were correlated with clinicopathologic outcomes and postoperative survival.ResultsTim-3 protein was over-expressed in bladder cancer cells, tumor infiltrating lymphocytes and endothelial cells from patients with BUC. The expression levels of Tim-3 were significantly correlated with advanced pathological grade and T stage. Moreover, another immune checkpoint molecule programmed death receptor-1(PD-1) was also over- expressed in BUC tissues and had a significant correlation with Tim-3. Multivariate analysis showed that Tim-3 expression, as well as PD-1 expression was both independent predictors of disease-free survival and overall survival in patients with BUC.Conclusion Tim-3 over-expression implies adverse clinical outcomes for BUC, which suggests it is a potential prognostic biomarker and a novel therapeutic target in BUC. J. Surg. Oncol. © 2015 Wiley Periodicals, Inc.
    Journal of Surgical Oncology 08/2015; 112(4). DOI:10.1002/jso.24012 · 3.24 Impact Factor
  • Lun Yu · Yonghua Wang · Shixiu Shao · Meng Yang · Haitao Niu · Qinchao Yu · Xinshen Wang ·
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    ABSTRACT: The stimulatory and inhibitory coreceptors expressed by T lymphocytes are known to play critical roles in regulating cancer immunity. An array of inhibitory coreceptors involved in the inhibition of T-cell functions and the blockade of immune activation have been discovered in recent years, the most important of which are cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmmed death-1 (PD-1), and B7 homolog 1 (B7-H1). Immunotherapies targeting T-cell coinhibitory molecules have proved to be effective in cancer treatment. Several kinds of monoclonal antibodies have been tested in preclinical studies, with better outcomes than conventional therapies in many malignancies. Common urological malignancies including renal cell carcinoma, bladder cancer and prostate cancer are supposed to be immunogenic cancer types and not so sensitive to conventional therapies as other malignancies. This review will focus on B7-H1/PD-1 blockade therapy in urological malignancies, summarizing the results of clinical trials as well as the challenges and prospects of this emerging immunotherapy.
    05/2015; DOI:10.5301/tj.5000326
  • Yonghua Wang · Meng Yang · Qinchao Yu · Lun Yu · Shixiu Shao · Xinsheng Wang ·
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    ABSTRACT: Bacillus Calmette-Guérin (BCG) has been used in the intravesical treatment of urothelial bladder cancer (UBC) for three decades. Despite its efficacy, intravesical BCG therapy is associated with some limitations such as side effects and BCG failure, which have inspired multiple ways to improve it. Recent advances have focused on recombinant BCG (rBCG) which provides a novel tactic for modification of BCG. To date, a number of rBCG strains have been developed and demonstrated to encourage efficacy and safety in preclinical and clinical studies. This review summarizes current rBCG strategies, concerns and future directions in UBC immunotherapy with an intention to encourage further research and eventually to inform clinical decisions.
    Expert Review of Anti-infective Therapy 09/2014; 15(1):1-9. DOI:10.1586/14737140.2015.961430 · 3.46 Impact Factor
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    ABSTRACT: Objective The aim of this study was to examine whether short hairpin RNA (shRNA) expressing lentiviral particles targeting B7-H1 infection could result in B7-H1 knockdown on dendritic cells (DCs) and to investigate whether B7-H1 silencing could augment the immune function of DCs and further elicit a more potent anti-tumor immune effect against bladder cancer cells in vitro. Methods Monocyte-derived DCs, which were generated from peripheral blood mononuclear cells, were infected by a recombinant lentivirus containing shRNA sequence aimed at B7-H1. After that, the infected DCs were pulsed by tumor antigens and used to stimulate cytotoxic T lymphocytes-based anti-tumor effect in vitro. Results The lentivirus-mediated shRNA delivery method efficiently and effectively silenced B7-H1 in DCs. Furthermore, the B7-H1 silencing enhanced the stimulatory capacity and the secretion of interleukin-12, but down-regulated interleukin-10 secretion. And more importantly, the anti-tumor effect of bladder cancer antigen-loaded DC vaccine in vitro was also potentially augmented. Conclusion This study suggests that a combination of B7-H1 knockdown and target antigen delivery could augment anti-tumor effects in vitro, which potentially provides a novel strategy in the immunotherapy of bladder cancer.
    OncoTargets and Therapy 08/2014; 7:1389-96. DOI:10.2147/OTT.S65367 · 2.31 Impact Factor
  • Chuanbiao Ji · Yonghua Wang · Qinchao Yu · Jing Liu · Yanan Liu · Jie Cui ·
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    ABSTRACT: Objective The aim of this study was to study the expression and the clinical significance of B7-H1 on dendritic cells (DCs) in peripheral blood from patients with bladder cancer. Methods Peripheral blood mononuclear cell were disparted from 30 bladder cancer patients and 7 healthy controls by density gradient centrifugation and then co-cultured. The expression of B7-H1 on DCs were analyzed by flow cytometry. Results Expression of B7-H1 on DCs in bladder cancer was higher than healthy controls (P < 0.01). And the expression were strongly associated with the pathological grade and clinical stage of bladder cancer (P < 0.05). Conclusion The up-regulation of B7-H1 on DCs was strongly associated with neoplastic progression of bladder cancer. B7-H1/programmed death (PD)-1 signal pathway may also play an important role in immune escape of bladder cancer during initial phase of T cell immune response.
    The Chinese-German Journal of Clinical Oncology 06/2013; 12(6). DOI:10.1007/s10330-012-1171-x