Original Article

Cancer Immunology, Immunotherapy

, Volume 57, Issue 12, pp 1757-1769

Virulizin® induces production of IL-17E to enhance antitumor activity by recruitment of eosinophils into tumors

  • Tania BenatarAffiliated withResearch and Development Department, Lorus Therapeutics Inc.
  • , Ming Y. CaoAffiliated withResearch and Development Department, Lorus Therapeutics Inc.BGTD, Health Canada Email author 
  • , Yoon LeeAffiliated withResearch and Development Department, Lorus Therapeutics Inc. Email author 
  • , Hui LiAffiliated withResearch and Development Department, Lorus Therapeutics Inc.
  • , Ningping FengAffiliated withResearch and Development Department, Lorus Therapeutics Inc.
  • , Xiaoping GuAffiliated withResearch and Development Department, Lorus Therapeutics Inc.
  • , Vivian LeeAffiliated withResearch and Development Department, Lorus Therapeutics Inc.
  • , Hongnan JinAffiliated withResearch and Development Department, Lorus Therapeutics Inc.
  • , Ming WangAffiliated withResearch and Development Department, Lorus Therapeutics Inc.
    • , Sandy DerAffiliated withDepartment of Laboratory Medicine and Pathobiology, Program in Proteomics and Bioinformatics, University of Toronto
    • , Jeff LightfootAffiliated withResearch and Development Department, Lorus Therapeutics Inc.
    • , Jim A. WrightAffiliated withResearch and Development Department, Lorus Therapeutics Inc.
    • , Aiping H. YoungAffiliated withResearch and Development Department, Lorus Therapeutics Inc.

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Abstract

Virulizin® has demonstrated strong antitumor efficacy in a variety of human tumor xenograft models including melanoma, pancreatic cancer, breast cancer, ovarian cancer and prostate cancer. Our previous studies have demonstrated that macrophages, NK cells, and cytokines are important in the antitumor mechanism of Virulizin®. Virulizin® treatment of tumor bearing mice results in the expansion as well as increased activity of monocytes/macrophages and production of cytokines IL-12 and TNFα and activation of NK cells. In this study we show that the inflammatory cytokine IL-17E (IL-25) is induced by Virulizin® treatment and is part of its antitumor mechanism. IL-17E is a proinflammatory cytokine, which induces a TH2 type immune response, associated with eosinophil expansion and infiltration into mucosal tissues. IL-17E was increased in sera of Virulizin®-treated mice bearing human melanoma xenografts, compared to saline-treated controls, as shown by 2D gel electrophoresis and ELISA. Treatment of splenocytes in vitro with Virulizin® resulted in increased IL-17E mRNA expression, which peaked between 24 and 32 h post-stimulation. Both in vitro and in vivo experiments demonstrated that B cells produced IL-17E in response to Virulizin® treatment. Furthermore, Virulizin® treatment in vivo resulted in increased blood eosinophilia and eosinophil infiltration into tumors. Finally, injection of recombinant IL-17E showed antitumor activity towards xenografted tumors, which correlated with increased eosinophilia in blood and tumors. Taken together, these results support another antitumor mechanism mediated by Virulizin®, through induction of IL-17E by B cells, leading to recruitment of eosinophils into tumors, which may function in parallel with macrophages and NK cells in mediating tumor destruction.

Keywords

Cancer Eosinophils IL-17E Immunotherapy Virulizin®