Virulizin induces production of IL-17E to enhance antitumor activity by recruitment of eosinophils into tumors.
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 TNFalpha 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 T(H)2 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.
Benatar
Tania
T
Research and Development Department, Lorus Therapeutics Inc., 2 Meridian Road, Toronto, ON, Canada, M9W 4Z7.
Cao
Ming Y
MY
Lee
Yoon
Y
Li
Hui
H
Feng
Ningping
N
Gu
Xiaoping
X
Lee
Vivian
V
Jin
Hongnan
H
Wang
Ming
M
Der
Sandy
S
Lightfoot
Jeff
J
Wright
Jim A
JA
Young
Aiping H
AH
D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D001646:Bile; D015153:Blotting, Western; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D015180:Electrophoresis, Gel, Two-Dimensional; D004797:Enzyme-Linked Immunosorbent Assay; D004804:Eosinophils / Q000187:drug effects*; D005434:Flow Cytometry; D006801:Humans; D020381:Interleukin-17 / Q000096:biosynthesis*; D008546:Melanoma, Experimental / Q000188:drug therapy*; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014020:Tissue Extracts / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D020381:Interleukin-17; D014020:Tissue Extracts; C087098:virulizin