Locally Targeting the IL-17/IL-17RA Axis Reduced Tumor Growth in a Murine B16F10 Melanoma Model

Ya-Shan Chen; Tse-Hung Huang; Chao-Lin Liu; Hui-Shan Chen; Meng-Hua Lee; Hsin-Wei Chen; Chia-Rui Shen

doi:10.1089/hum.2018.104

Locally Targeting the IL-17/IL-17RA Axis Reduced Tumor Growth in a Murine B16F10 Melanoma Model

Hum Gene Ther. 2019 Mar;30(3):273-285. doi: 10.1089/hum.2018.104. Epub 2018 Oct 3.

Authors

Ya-Shan Chen^{1

2}, Tse-Hung Huang^{3

4}, Chao-Lin Liu^{5

6}, Hui-Shan Chen¹, Meng-Hua Lee^{1

2}, Hsin-Wei Chen^{7

8}, Chia-Rui Shen^{1

2

9

10}

Affiliations

¹ 1 Department and Graduate Institute of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan, ROC.
² 2 Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan, ROC.
³ 3 School of Traditional Chinese Medicine, Chang Gung University, Taoyuan, Taiwan, ROC.
⁴ 4 Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan, ROC.
⁵ 5 College of Engineering, Chang Gung University, Taoyuan, Taiwan, ROC.
⁶ 6 Department of Chemical Engineering, Ming Chi University of Technology, New Taipei, Taiwan, ROC.
⁷ 7 National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli, Taiwan, ROC.
⁸ 8 Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, ROC.
⁹ 9 Department of Ophthalmology, Lin-Kou Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC.
¹⁰ 10 Chang Gung Immunology Consortium, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan, ROC.

PMID: 30079767
DOI: 10.1089/hum.2018.104

Abstract

Interleukin (IL)-17 and the cells that produce it within the tumor microenvironment appear to promote tumor development and are associated with survival in cancer patients. Here we investigated the role of the IL-17/IL-17 receptor A (IL-17RA) axis in regulating melanoma progression and evaluated the therapeutic potential of blocking the IL-17/IL-17RA pathway. First, recombinant mouse IL-17 (γmIL-17) treatment significantly increased proliferation of mouse B16F10 cells and human A375 and A2058 cells. Silencing IL-17RA by small hairpin RNA (shRNA) in B16F10 cells reduced the γmIL-17-elicited cell proliferation, migration, and invasion, and significantly reduced vascular endothelial growth factor and matrix metalloproteinase production. Remarkably, knockdown of IL-17RA led to a significantly decreased capability of B16F10 cells to form tumors in vivo, similar to that in IL-17-deficient mice. Finally, local application of an adenovirus delivering a shRNA against IL-17RA mRNA not only significantly suppressed tumor development, but also enhanced antitumor immunity by increasing the interferon γ-expressing T cells and not T regulatory cells. Our results highlight the critical role of the IL-17/IL-17RA pathway in tumor progression and imply that targeting IL-17RA represents a promising therapeutic strategy.

Keywords: IL-17; IL-17RA; adenovirus; gene therapy; melanoma; shRNA.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenoviridae / genetics
Animals
Cell Cycle / genetics
Cell Line, Tumor
Cell Movement / genetics
Cell Proliferation / genetics
Disease Models, Animal
Gene Targeting* / methods
Genetic Vectors / genetics
Humans
Interleukin-17 / genetics*
Interleukin-17 / metabolism
Melanoma, Experimental / drug therapy
Melanoma, Experimental / genetics*
Melanoma, Experimental / metabolism
Melanoma, Experimental / pathology*
Mice
Mice, Knockout
Neoplasm Metastasis
RNA Interference
RNA, Small Interfering / administration & dosage
RNA, Small Interfering / genetics
Receptors, Interleukin-17 / genetics*
Receptors, Interleukin-17 / metabolism
Signal Transduction / drug effects*
Tumor Burden

Substances

Interleukin-17
RNA, Small Interfering
Receptors, Interleukin-17