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.
Get full access to this article
View all access options for this article.
References
1.
BalkwillF, MantovaniA. Inflammation and cancer: back to Virchow?. Lancet, 2001; 357:539–545.
2.
LiY, ZhangJ, MaH. Chronic inflammation and gallbladder cancer. Cancer Lett, 2014; 345:242–248.
3.
TangX. Tumor-associated macrophages as potential diagnostic and prognostic biomarkers in breast cancer. Cancer Lett, 2013; 332:3–10.
4.
TanW, ZhangW, StrasnerA, et al.Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature, 2011; 470:548–553.
5.
MaoY, KellerET, GarfieldDH, et al.Stromal cells in tumor microenvironment and breast cancer. Cancer Metastasis Rev, 2013; 32:303–315.
6.
WhitesideTL. The tumor microenvironment and its role in promoting tumor growth. Oncogene, 2008; 27:5904–5912.
7.
BierieB, MosesHL. Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer, 2006; 6:506–520.
8.
YangL, PangY, MosesHL. TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression. Trends Immunol, 2010; 31:220–227.
9.
KryczekI, WeiS, ZouL, et al.Cutting edge: Th17 and regulatory T cell dynamics and the regulation by IL-2 in the tumor microenvironment. J Immunol, 2007; 178:6730–6733.
10.
MiyaharaY, OdunsiK, ChenW, et al.Generation and regulation of human CD4+ IL-17-producing T cells in ovarian cancer. Proc Natl Acad Sci U S A, 2008; 105:15505–15510.
11.
ChenX, WanJ, LiuJ, et al.Increased IL-17-producing cells correlate with poor survival and lymphangiogenesis in NSCLC patients. Lung Cancer, 2010; 69:348–354.
12.
ChenYS, LiuCL, LeeMH, et al.The role of Tc17 in cancer immunity and clinical associations. Journal of Biomedical & Laboratory Sciences, 2013; 25:77–83.
13.
ZhangB, RongG, WeiH, et al.The prevalence of Th17 cells in patients with gastric cancer. Biochem Biophys Res Commun, 2008; 374:533–537.
14.
TsaiJP, LeeMH, HsuSC, et al.CD4+ T cells disarm or delete cytotoxic T lymphocytes under IL-17-polarizing conditions. J Immunol, 2012; 189:1671–1679.
15.
LeeMH, Tung-Chieh ChangJ, LiaoCT, et al.Interleukin 17 and peripheral IL-17-expressing T cells are negatively correlated with the overall survival of head and neck cancer patients. Oncotarget, 2018; 9:9825–9837.
16.
LiuJ, DuanY, ChengX, et al.IL-17 is associated with poor prognosis and promotes angiogenesis via stimulating VEGF production of cancer cells in colorectal carcinoma. Biochem Biophys Res Commun, 2011; 407:348–354.
17.
LiQ, LiQ, ChenJ, et al.Prevalence of Th17 and Treg cells in gastric cancer patients and its correlation with clinical parameters. Oncol Rep, 2013; 30:1215–1222.
18.
KryczekI, BanerjeeM, ChengP, et al.Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. Blood, 2009; 114:1141–1149.
19.
DuWJ, ZhenJH, ZengZQ, et al.Expression of interleukin-17 associated with disease progression and liver fibrosis with hepatitis B virus infection: IL-17 in HBV infection. Diagn Pathol, 2013; 8:40.
20.
CurtisMM, WaySS. Interleukin-17 in host defence against bacterial, mycobacterial and fungal pathogens. Immunology, 2009; 126:177–185.
21.
MatsuzakiG, UmemuraM. Interleukin-17 as an effector molecule of innate and acquired immunity against infections. Microbiol Immunol, 2007; 51:1139–1147.
22.
ZhaoL, TangY, YouZ, et al.Interleukin-17 contributes to the pathogenesis of autoimmune hepatitis through inducing hepatic interleukin-6 expression. PLoS One, 2011; 6:e18909.
23.
OguraH, MurakamiM, OkuyamaY, et al.Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction. Immunity, 2008; 29:628–636.
24.
WitowskiJ, KsiazekK, JorresA. Interleukin-17: a mediator of inflammatory responses. Cell Mol Life Sci, 2004; 61:567–579.
25.
GuFM, LiQL, GaoQ, et al.IL-17 induces AKT-dependent IL-6/JAK2/STAT3 activation and tumor progression in hepatocellular carcinoma. Mol Cancer, 2011; 10:150.
26.
WangL, YiT, KortylewskiM, et al.IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway. J Exp Med, 2009; 206:1457–1464.
27.
NumasakiM, FukushiJ, OnoM, et al.Interleukin-17 promotes angiogenesis and tumor growth. Blood, 2003; 101:2620–2627.
28.
TakahashiH, NumasakiM, LotzeMT, et al.Interleukin-17 enhances bFGF-, HGF- and VEGF-induced growth of vascular endothelial cells. Immunol Lett, 2005; 98:189–193.
29.
WuX, ChenX, ZhouQ, et al.Hepatocyte growth factor activates tumor stromal fibroblasts to promote tumorigenesis in gastric cancer. Cancer Lett, 2013; 335:128–135.
30.
LereclusE, ToutM, GiraultA, et al.A possible association of baseline serum IL-17A concentrations with progression-free survival of metastatic colorectal cancer patients treated with a bevacizumab-based regimen. BMC Cancer, 2017; 17:220.
31.
IbrahimS, GiraultA, OhresserM, et al.Monoclonal antibodies targeting the IL-17/IL-17RA axis: an opportunity to improve the efficiency of anti-VEGF therapy in fighting metastatic colorectal cancer?. Clin Colorectal Cancer, 2018; 17:e109-e113.
32.
WangL, YiT, ZhangW, et al.IL-17 enhances tumor development in carcinogen-induced skin cancer. Cancer Res, 2010; 70:10112–10120.
33.
DayYJ, LiouJT, LeeCM, et al.Lack of interleukin-17 leads to a modulated micro-environment and amelioration of mechanical hypersensitivity after peripheral nerve injury in mice. Pain, 2014; 155:1293–1302.
34.
PanWY, LoCH, ChenCC, et al.Cancer immunotherapy using a membrane-bound interleukin-12 with B7-1 transmembrane and cytoplasmic domains. Mol Ther, 2012; 20:927–937.
35.
YangWC, HwangYS, ChenYY, et al.Interleukin-4 supports the suppressive immune responses elicited by regulatory T cells. Front Immunol, 2017; 8:1508.
36.
HeD, LiH, YusufN, et al.IL-17 mediated inflammation promotes tumor growth and progression in the skin. PLoS One, 2012; 7:e32126.
37.
EgebladM, WerbZ. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer, 2002; 2:161–174.
38.
WrightJF, BennettF, LiB, et al.The human IL-17F/IL-17A heterodimeric cytokine signals through the IL-17RA/IL-17RC receptor complex. J Immunol, 2008; 181:2799–2805.
39.
MayMJ. IL-17R signaling: new players get in on the Act1. Nat Immunol, 2011; 12:813–815.
40.
de VrijJ, WillemsenRA, LindholmL, et al.Adenovirus-derived vectors for prostate cancer gene therapy. Hum Gene Ther, 2010; 21:795–805.
41.
MajhenD, CalderonH, ChandraN, et al.Adenovirus-based vaccines for fighting infectious diseases and cancer: progress in the field. Hum Gene Ther, 2014; 25:301–317.
42.
MengY, BeckettMA, LiangH, et al.Blockade of tumor necrosis factor alpha signaling in tumor-associated macrophages as a radiosensitizing strategy. Cancer Res, 2010; 70:1534–1543.
43.
WuS, RheeKJ, AlbesianoE, et al.A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat Med, 2009; 15:1016–1022.
44.
HayataK, IwahashiM, OjimaT, et al.Inhibition of IL-17A in tumor microenvironment augments cytotoxicity of tumor-infiltrating lymphocytes in tumor-bearing mice. PLoS One, 2013; 8:e53131.
45.
Martin-OrozcoN, MuranskiP, ChungY, et al.T helper 17 cells promote cytotoxic T cell activation in tumor immunity. Immunity, 2009; 31:787–798.
46.
YuY, ChoHI, WangD, et al.Adoptive transfer of Tc1 or Tc17 cells elicits antitumor immunity against established melanoma through distinct mechanisms. J Immunol, 2013; 190:1873–1881.
47.
BenchetritF, CireeA, VivesV, et al.Interleukin-17 inhibits tumor cell growth by means of a T-cell-dependent mechanism. Blood, 2002; 99:2114–2121.
48.
HiraharaN, NioY, SasakiS, et al.Inoculation of human interleukin-17 gene-transfected Meth-A fibrosarcoma cells induces T cell-dependent tumor-specific immunity in mice. Oncology, 2001; 61:79–89.
49.
KatoT, FurumotoH, OguraT, et al.Expression of IL-17 mRNA in ovarian cancer. Biochem Biophys Res Commun, 2001; 282:735–738.
50.
Silva-SantosB. Promoting angiogenesis within the tumor microenvironment: the secret life of murine lymphoid IL-17-producing gammadelta T cells. Eur J Immunol, 2010; 40:1873–1876.
51.
ChungAS, WuX, ZhuangG, et al.An interleukin-17-mediated paracrine network promotes tumor resistance to anti-angiogenic therapy. Nat Med, 2013; 19:1114–1123.
52.
HotchkissKA, AshtonAW, MahmoodR, et al.Inhibition of endothelial cell function in vitro and angiogenesis in vivo by docetaxel (Taxotere): association with impaired repositioning of the microtubule organizing center. Mol Cancer Ther, 2002; 1:1191–1200.
53.
LiJ, LauGK, ChenL, et al.Interleukin 17A promotes hepatocellular carcinoma metastasis via NF-kB induced matrix metalloproteinases 2 and 9 expression. PLoS One, 2011; 6:e21816.
54.
KessenbrockK, PlaksV, WerbZ. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell, 2010; 141:52–67.
55.
LittlepageLE, SternlichtMD, RougierN, et al.Matrix metalloproteinases contribute distinct roles in neuroendocrine prostate carcinogenesis, metastasis, and angiogenesis progression. Cancer Res, 2010; 70:2224–2234.
56.
IkedaH, OldLJ, SchreiberRD. The roles of IFN gamma in protection against tumor development and cancer immunoediting. Cytokine Growth Factor Rev, 2002; 13:95–109.
57.
HeD, LiH, YusufN, et al.IL-17 promotes tumor development through the induction of tumor promoting microenvironments at tumor sites and myeloid-derived suppressor cells. J Immunol, 2010; 184:2281–2288.
58.
ZhaoQ, XiaoX, WuY, et al.Interleukin-17-educated monocytes suppress cytotoxic T-cell function through B7-H1 in hepatocellular carcinoma patients. Eur J Immunol, 2011; 41:2314–2322.
59.
ShenCR, YangWC, ChenHW. The fate of regulatory T cells: survival or apoptosis. Cell Mol Immunol, 2014; 11:11–13.
60.
GabrilovichDI, NagarajS. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol, 2009; 9:162–174.
61.
QuP, WangLZ, LinPC. Expansion and functions of myeloid-derived suppressor cells in the tumor microenvironment. Cancer Lett, 2016; 380:253–256.
62.
GanesanAP, JohanssonM, RuffellB, et al.Tumor-infiltrating regulatory T cells inhibit endogenous cytotoxic T cell responses to lung adenocarcinoma. J Immunol, 2013; 191:2009–2017.
63.
MarabelleA, KohrtH, Sagiv-BarfiI, et al.Depleting tumor-specific Tregs at a single site eradicates disseminated tumors. J Clin Invest, 2013; 123:2447–2463.
64.
LiX, KostareliE, SuffnerJ, et al.Efficient Treg depletion induces T-cell infiltration and rejection of large tumors. Eur J Immunol, 2010; 40:3325–3335.
65.
YangZ, ZhangB, LiD, et al.Mast cells mobilize myeloid-derived suppressor cells and Treg cells in tumor microenvironment via IL-17 pathway in murine hepatocarcinoma model. PLoS One, 2010; 5:e8922.
66.
LiYQ, LiuFF, ZhangXM, et al.Tumor secretion of CCL22 activates intratumoral Treg infiltration and is independent prognostic predictor of breast cancer. PLoS One, 2013; 8:e76379.
67.
AlbiniA, BrunoA, NoonanDM, et al.Contribution to tumor angiogenesis from innate immune cells within the tumor microenvironment: implications for immunotherapy. Front Immunol, 2018; 9:527.
68.
ZhengX, TurkowskiK, MoraJ, et al.Redirecting tumor-associated macrophages to become tumoricidal effectors as a novel strategy for cancer therapy. Oncotarget, 2017; 8:48436–48452.
69.
ChenYS, ShenCR. Immune checkpoint blockade therapy: the 2014 Tang Prize in Biopharmaceutical Science. Biomed J, 2015; 38:5–8.
70.
HuSL, AbramsK, BarberGN, et al.Protection of macaques against SIV infection by subunit vaccines of SIV envelope glycoprotein gp160. Science, 1992; 255:456–459.
71.
XiangB, BaybuttTR, Berman-BootyL, et al.Prime-boost immunization eliminates metastatic colorectal cancer by producing high-avidity effector CD8(+) T cells. J Immunol, 2017; 198:3507–3514.
72.
WargowskiE, JohnsonLE, EickhoffJC, et al.Prime-boost vaccination targeting prostatic acid phosphatase (PAP) in patients with metastatic castration-resistant prostate cancer (mCRPC) using Sipuleucel-T and a DNA vaccine. J Immunother Cancer, 2018; 6:21.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
