Application of genetically engineered Salmonella typhimurium for interferon-gamma–induced therapy against melanoma

Wonsuck Yoon, Yoo Chang Park, Jinseok Kim, Yang Seok Chae, Jung Hye Byeon, Sang Hyun Min, Sungha Park, Young Yoo, Yong Keun Park, Byeong Mo Kim

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    75 Citations (Scopus)

    Abstract

    Salmonella have been experimentally used as anti-cancer agents, because they show selective growth in tumours. In this study, we genetically modified attenuated Salmonella typhimurium to express and secrete interferon-gamma (IFN-γ) as a tumouricidal agent to enhance the therapeutic efficacy of Salmonella. IFN-γ was fused to the N-terminal region (residues 1–160) of SipB (SipB160) for secretion from bacterial cells. Attenuated S. typhimurium expressing recombinant IFN-γ (S. typhimurium (IFN-γ)) invaded the melanoma cells and induced cytotoxicity. Subcutaneous administration of S. typhimurium (IFN-γ) also efficiently inhibited tumour growth and prolonged the survival of C57BL/6 mice bearing B16F10 melanoma compared with administration of phosphate-buffered saline (PBS), unmodified S. typhimurium or S. typhimurium expressing empty vector (S. typhimurium [Vec]) in a natural killer (NK) cell-dependent manner. Moreover, genetically modified Salmonella, including S. typhimurium (IFN-γ), showed little toxicity to normal tissues with no observable adverse effects. However, S. typhimurium (IFN-γ)-mediated tumour suppression was attributed to direct killing of tumour cells rather than to stable anti-tumour immunity. Collectively, these results suggest that tumour-targeted therapy using S. typhimurium (IFN-γ) has potential for melanoma treatment.

    Original languageEnglish
    Pages (from-to)48-61
    Number of pages14
    JournalEuropean Journal of Cancer
    Volume70
    DOIs
    Publication statusPublished - 2017 Jan 1

    Bibliographical note

    Funding Information:
    This work was supported by the NRF -Fund ( NRF-2013R1A1A2005567 , NRF-2015R1D1A4A01019910 , NRF-2012R1A1A2038549 ) and by a grant from the Korea University to W. Yoon and Y.K. Park. This study was also supported by a grant from the Korea Healthcare technology R&D Project , Ministry for Health & Welfare Affairs , Republic of Korea (No. HI08C2149 ) and by a faculty research grant from Yonsei University College of Medicine for 2015 (No. 2015-32-0059 ) to B.M. Kim.

    Publisher Copyright:
    © 2016 Elsevier Ltd

    Keywords

    • Genetically modified Salmonella typhimurium (S. typhimurium)
    • Interferon-gamma (IFN-γ)
    • Melanoma
    • SipB160
    • Treatment option for melanoma

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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