Immunodominant PstS1 antigen of mycobacterium tuberculosis is a potent biological response modifier for the treatment of bladder cancer

Christian, Sänger; Busche, Andreas; Gabriele, Bentien; Spallek, Ralf; Jonas, Friedrich; Böhle, Andreas; Singh, Mahavir; Brandau, Sven

doi:10.1186/1471-2407-4-86

Cited by 16 publications

(14 citation statements)

References 32 publications

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“…Based on initial data demonstrating the immunstimulatory potential of PstS-1 on PBMC’s and dendritic cells [10] we addressed the influence of PstS-1 on purified NK cells and monocytes and investigated whether the addition of PstS-1 to the NK-monocyte-co-culture would lead to further enhancement of different NK cell functions. Stimulation of purified monocytes with PstS-1 resulted in a significant dose-dependent release of IL-12 and IL-18 but not IL-15, while surface markers like CD11c, CD80 and CD86 remained unaffected (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…In tuberculosis disease PstS-1 is one of the most immunogenic antigens, and the 38 kDa-antigen is therefore included in serodiagnostic assays for active tuberculosis. Further, PstS-1 showed potent immunstimulatory capacity and antitumoural activity in bladder cancer and melanoma [10]. However, in ovarian cancer PstS-1 has not been studied so far.…”

Section: Introductionmentioning

confidence: 99%

“…However, in ovarian cancer PstS-1 has not been studied so far. In vitro assays demonstrated stimulating effects of PstS-1 on peripheral blood mononuclear cells (PBMC’s) [10]. In monocytes PstS-1-signals via toll-like-receptors (TLR)-2 and TLR-4 activated ERK1/2 and MAPK-pathways and enhanced the production of IL-6 and TNFα [11,12].…”

Section: Introductionmentioning

confidence: 99%

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Monocytes and the 38kDa-antigen of mycobacterium tuberculosis modulate natural killer cell activity and their cytolysis directed against ovarian cancer cell lines

et al. 2012

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BackgroundDespite strong efforts to improve clinical outcome of ovarian cancer patients by conventional and targeted immuno-based therapies, the prognosis of advanced ovarian cancer is still poor. Natural killer (NK) cells mediate antibody-dependent cellular cytotoxicity (ADCC), release immunostimulatory cytokines and thus function as potent anti-tumour effector cells. However, tumour cells developed mechanisms to escape from an effective immune response. So highly immunogenic substances, like the 38 kDa-preparation of M. tuberculosis, PstS-1, are explored for their potential to enhance cancer-targeted immune responses. In this study we examined the modulation of different NK cell functions by accessory monocytes and PstS-1. We focussed on NK cell activation as well as natural and antibody-dependent cellular cytotoxicity directed against epidermal-growth-factor-receptor (EGFR)-positive ovarian cancer cell lines.MethodsActivation, cytokine release and cytotoxicity of NK cells stimulated by monocytes and PstS-1 were determined by FACS-analysis, ELISA, Bioplex assay and quantitative polymerase-chain reaction (qPCR). Transwell assays were used to discriminate cell-cell contact-dependent from contact-independent mechanisms. Five ovarian cancer cell lines (A2780, IGROV-1, OVCAR-3, OVCAR-4 and SKOV-3) with different EGFR-expression were used as target cells for natural and antibody-dependent cellular cytotoxicity assays. Cetuximab (anti-EGFR-antibody) was used for ADCC studies.ResultsOur data show that monocytes effectively enhance activation as well natural and antibody-dependent cytolytic activity of NK cells. PstS-1 directly stimulated monocytes and further activated monocyte-NK-co-cultures. However, PstS-1 did not directly influence purified NK cells and did also not affect natural and antibody-dependent cellular cytotoxicity directed against EGFR-positive ovarian cancer cells, even in presence of monocytes. Direct cell-cell contact between NK cells and monocytes was required for NK activation, while released cytokines seemed to play a minor role.ConclusionsOur data suggest that monocytes enhance natural and antibody-dependent cytotoxic activity of NK cells in a cell-cell contact dependent manner. The TLR-agonist PstS-1 provides additional monocyte activation and induces NK activation markers, while NK cytotoxicity remains unaffected. We conclude that monocytes provide accessory function for ADCC exerted by NK during antibody-based cancer immunotherapy directed against EGFR-positive ovarian cancer cells.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Monocytes and the 38kDa-antigen of mycobacterium tuberculosis modulate natural killer cell activity and their cytolysis directed against ovarian cancer cell lines

et al. 2012

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“…When the 38 kDa antigen was studied, a cytotoxic activity against T24 BC cells was observed in 38 kDa antigen-activated peripheral blood mononuclear cells (PBMC), also in a dose-dependent manner. Again, 38 kDa antigen-intravesically treated tumor-bearing mice survived longer than non-treated tumor-bearing mice [44], triggering a systemic response observed when splenocytes from treated mice respond specifically to the instilled antigen. Different works have evaluated the antitumor capacity of Ag85.…”

Section: Purified Mycobacteria Antigens and Non-viable Mycobacteriamentioning

confidence: 98%

Mycobacteria-Derived Agents for the Treatment of Urological and Renal Cancers

Noguera-Ortega¹,

Julián²

2018

Mycobacterium - Research and Development

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Mycobacteria are the unique group of bacteria that are currently used in antitumoral immunotherapy. Specifically, intravesical instillation of viable cells of Mycobacterium bovis Bacillus Calmette-Guérin (BCG), after transurethral resection of non-muscle invasive bladder cancer, is the most efficacious treatment for avoiding recurrence and progression of the disease. BCG has been used for the last 35 years for bladder cancer treatment, but other mycobacteria or mycobacteria components are currently under preclinical and clinical studies for the immunotherapeutic treatment of non-invasive bladder cancer and also of other types of tumors located at the urinary system. Those are, for instance, cell wall extracts or heat-killed forms from BCG or other mycobacteria such as Mycobacterium phlei or Mycobacterium indicus pranii (MIP) or even viable cells from non-pathogenic mycobacteria such us Mycobacterium brumae. A review of the literature in which mycobacteria components, non-viable mycobacteria, and viable mycobacteria have been used for these different cancers will be performed. In this chapter, the function of mycobacteria as antitumor agents will be then analyzed, awarding the audience a broad knowledge of one of the beneficial applications of mycobacteria, which are usually introduced as dangerous microorganisms.

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“…Lastly, rBCG strategies utilizing various other BCG subunit proteins and antigens such as PstS1, MPT-64, and Ag85B have been evaluated and show efficacy in enhancing cytotoxicity on superficial bladder cancers in both in vitro and orthotopic murine bladder models [Sanger et al 2004;Yu et al 2007;Begnini et al 2013]. Interestingly, poly-rBCG DNA vaccines that specify multiple BCG antigens such as Ag85A, Ag85B, Mpt64, and PstS3 have been developed and shown to elicit Th1-predominant immune responses, inhibit tumor growth, and prolong the survival of bladder tumor bearing mice [Lee et al 2004].…”

Section: Bcg Subcomponent-based Rbcgmentioning

confidence: 99%

Novel immunotherapeutic approaches to the treatment of urothelial carcinoma

Muthigi

George

Brancato

et al. 2016

Therapeutic Advances in Urology

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Abstract:Immunotherapy has long played a role in urothelial cancers with the use of bacille Calmette Guérin (BCG) being a mainstay in the treatment of nonmuscle invasive bladder cancer. Novel therapeutic approaches have not significantly impacted mortality in this population and so a renaissance in immunotherapy has resulted. This includes recombinant BCG, oncolytic viruses, monoclonal antibodies, vaccines, and adoptive T-cell therapy. Herein, we provide a review of the current state of the art and future therapies regarding immunotherapeutic strategies for urothelial carcinoma.

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Immunodominant PstS1 antigen of mycobacterium tuberculosis is a potent biological response modifier for the treatment of bladder cancer

Cited by 16 publications

References 32 publications

Monocytes and the 38kDa-antigen of mycobacterium tuberculosis modulate natural killer cell activity and their cytolysis directed against ovarian cancer cell lines

Monocytes and the 38kDa-antigen of mycobacterium tuberculosis modulate natural killer cell activity and their cytolysis directed against ovarian cancer cell lines

Mycobacteria-Derived Agents for the Treatment of Urological and Renal Cancers

Novel immunotherapeutic approaches to the treatment of urothelial carcinoma

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