IL-17E, a proinflammatory cytokine, has antitumor efficacy against several tumor types in vivo.
Interleukin-17E (IL-17E) belongs to a novel family of cytokines that possess significant homology to IL-17. IL-17E has potent inflammatory effects in vitro and in vivo. Overexpression of IL-17E in mice results in a T helper-2 (Th2)-type immune response, which includes the expansion of eosinophils through the production of IL-5, and elevated gene expression of IL-4 and IL-13 in multiple tissues. In this study, we show that IL-17E has antitumor activity in vivo, a previously unrecognized function of IL-17E. Antitumor efficacy of IL-17E was examined in a variety of human tumor xenograft models, including melanoma, breast, lung, colon, and pancreatic cancers. Injection of recombinant IL-17E every other day resulted in significant antitumor activity in these tumor models. In addition, the combination of IL-17E with chemotherapy or immunotherapy agents showed an enhanced antitumor efficacy in human tumor xenograft models in mice as compared to either agent alone. Antitumor activity was demonstrated using different routes of administration, including intraperitoneal, intravenous, and subcutaneous injection. Anticancer activity was shown for both mouse and human forms of IL-17E, which have a high degree of sequence identity. Tumor-bearing mice treated with IL-17E showed a significant increase in serum levels of IL-5 and increased numbers of eosinophils in peripheral blood compared to the control group. Spleens isolated from IL-17E-treated mice showed a significant increase in eosinophils that correlated with antitumor activity of IL-17E in a dose-response manner. Finally, we demonstrate that B cells are necessary for IL-17E-mediated antitumor activity and that IL-17E was found to activate signaling pathways in B cells in vitro. Taken together, these data demonstrate that IL-17E has antitumor activity in vivo, and support further investigation of the potential clinical use of IL-17E as an anticancer agent.
Benatar
Tania
T
Research and Development Department, Lorus Therapeutics Inc., 2 Meridian Road, Toronto, ON, M9W 4Z7, Canada. tbenatar@rogers.com
Cao
Ming Y
MY
Lee
Yoon
Y
Lightfoot
Jeff
J
Feng
Ningping
N
Gu
Xiaoping
X
Lee
Vivian
V
Jin
Hongnan
H
Wang
Ming
M
Wright
Jim A
JA
Young
Aiping H
AH
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004802:Eosinophilia / Q000276:immunology; D005260:Female; D019073:HT29 Cells; D006801:Humans; D007091:Image Processing, Computer-Assisted; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D015848:Interleukin-5 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D020381:Interleukin-17; D015848:Interleukin-5