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Mycobacterial extracellular vesicles (MEVs) as a novel option in bladder cancer therapy

R Sorrentino(1) P Miotto(1) C Venegoni(2) F Pederzoli(2) V Murdica(2) A Salonia(2) D M Cirillo(1) M Alfano(2)

1:San Raffael Scientific Institute; 2:Urological Research Institute (URI-HSR)

The intravesical instillation of the BCG vaccine (attenuated Mycobacterium bovis) after the transurethral resection of bladder tumour is the gold-standard treatment for patients with high-risk non-muscle invasive bladder cancer (NMIBC). Nevertheless, only about 50% of patients show a complete response to BCG treatment, and mild to severe side effects are very common. Extracellular vesicles (EVs) from mycobacteria (MEVs) have recently been shown to play a role during mycobacteria infection.  

In this study, we characterized MEVs and their effect on bladder cancer cell lines (BCaCL).

MEVs were isolated from BCG and Mycobacterium tuberculosis H37Rv stationary-phase cultures and purified by size exclusion chromatography, next characterized physiochemically and expression of mycobacterial markers. Subsequently, different grade bladder cancer cell lines (BCaCL) were treated with 5 and 10 µg of MEVs or infected with viable BCG for 72 hr. BCaCL response was assessed by calcein assay and ELISA cytokines quantification.

Western Blot confirmed the purity of MEVs (LAM and LpqH positive; eukaryotic markers negative). Live BCG and BCG-MEVs displayed a degree of cytotoxic effect, but only H37Rv-MEVs showed a statistically significant cytotoxic against different BCaCL (p<0,05). Cytokine profiling highlighted a higher immunomodulatory capability of BCG-MEVs and H37Rv-MEVs compared to BCG infection (higher modulation of TNFα, IL-6, and IL-12).

Our results support the hypothesis that MEVs can mimic the effect of BCG while overcoming the side effects related to the use of viable bacteria for the treatment of NMIBC.

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