IL-25 blockade inhibits metastasis in breast cancer

Abstract

Metastasis is the leading cause of death in breast cancer patients. However, the mechanisms underlying metastasis are not well understood and there is no effective treatment in the clinic. Here, we demonstrate that in MMTVPyMT, a highly malignant spontaneous breast tumor model, IL-25 (also called IL-17E) was expressed by tumorinfiltrating CD4⁺ T cells and macrophages. An IL-25 neutralization antibody, while not affecting primary tumor growth, substantially reduced lung metastasis. Inhibition of IL-25 resulted in decreased type 2 T cells and macrophages in the primary tumor microenvironments, both reported to enhance breast tumor invasion and subsequent metastasis to the lung. Taken together, our data suggest IL-25 blockade as a novel treatment formetastatic breast tumor.

Keywords

IL-25 / breast cancer / metastasis / MMTVPyMT

References

[1] Angkasekwinai P, Park H, Wang YH, Wang YH, Chang SH, Corry DB, Liu YJ, Zhu Z, Dong C (2007) Interleukin 25 promotes the initiation of proallergic type 2 responses. J Exp Med 204:1509–1517

[2] Angkasekwinai P, Chang SH, Thapa M, Watarai H, Dong C (2010) Regulation of IL-9 expression by IL-25 signaling. Nat Immunol 11:250–256

[3] Angkasekwinai P, Srimanote P, Wang YH, Pootong A, Sakolvaree Y, Pattanapanyasat K, Chaicumpa W, Chaiyaroj S, Dong C (2013) Interleukin-25 (IL-25) promotes efficient protective immunity against Trichinella spiralis infection by enhancing the antigenspecific IL-9 response. Infect Immun 81:3731–3741

[4] Balkwill FR, Mantovani A (2012) Cancer-related inflammation: common themes and therapeutic opportunities. Semin Cancer Biol 22:33–40

[5] Barlow JL, McKenzie AN (2009) IL-25: a key requirement for the regulation of type-2 immunity. Biofactors 35:178–182

[6] Benatar T, Cao MY, Lee Y, Lightfoot J, Feng NP, Gu XP, Lee V, Jin HN, Wang M, Wright JA(2010) IL-17E, a proinflammatory cytokine, has antitumor efficacy against several tumor types in vivo. Cancer Immunol Immunother 59:805–817

[7] Cao Q, Wang C, Zheng D, Wang Y, Lee VW, Wang YM, Zheng G, Tan TK, Yu D, Alexander SI(2011) IL-25 induces M2 macrophages and reduces renal injury in proteinuric kidney disease. J Am Soc Nephrol 22:1229–1239

[8] Chambers AF, Groom AC, MacDonald IC (2002) Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2:563–572

[9] Coussens LM, Zitvogel L, Palucka AK (2013) Neutralizing tumorpromoting chronic inflammation: a magic bullet? Science 339:286–291

[10] D’Cruz CM, Gunther EJ, Boxer RB, Hartman JL, Sintasath L, Moody SE, Cox JD, Ha SI, Belka GK, Golant A (2001) c-MYC induces mammary tumorigenesis by means of a preferred pathway involving spontaneous Kras2 mutations. Nat Med 7:235–239

[11] DeNardo DG, Barreto JB, Andreu P, Vasquez L, Tawfik D, Kolhatkar N, Coussens LM (2009) CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell 16:91–102

[12] Di Cristofano A, Pandolfi PP (2000) The multiple roles of PTEN in tumor suppression. Cell 100:387–390

[13] Duan W, Mehta AK, Magalhaes JG, Ziegler SF, Dong C, Philpott DJ, Croft M (2010) Innate signals from Nod2 block respiratory tolerance and program T(H)2-driven allergic inflammation. J Allergy Clin Immunol 126(1284–1293):e1210

[14] Fahy JV (2015) Type 2 inflammation in asthma–present in most, absent in many. Nat Rev Immunol 15:57–65

[15] Fort MM, Cheung J, Yen D, Li J, Zurawski SM, Lo S, Menon S, Clifford T, Hunte B, Lesley R (2001) IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity 15:985–995

[16] Franklin RA, Liao W, Sarkar A, Kim MV, Bivona MR, Liu K, Pamer EG, Li MO (2014) The cellular and molecular origin of tumorassociated macrophages. Science 344:921–925

[17] Furuta S, Jeng YM, Zhou L, Huang L, Kuhn I, Bissell MJ, Lee WH (2011) IL-25 causes apoptosis of IL-25R-expressing breast cancer cells without toxicity to nonmalignant cells. Sci Transl Med 3:78ra31

[18] Giraudo E, Inoue M, Hanahan D (2004) An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis. J Clin Investig 114:623–633

[19] Gocheva V, Wang HW, Gadea BB, Shree T, Hunter KE, Garfall AL, Berman T, Joyce JA (2010) IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion. Genes Dev 24:241–255

[20] Guy CT, Cardiff RD, Muller WJ (1992a) Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol Cell Biol 12:954–961

[21] Guy CT, Webster MA, Schaller M, Parsons TJ, Cardiff RD, Muller WJ (1992b) Expression of the Neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. Proc Natl Acad Sci USA 89:10578–10582

[22] Hong JY, Bentley JK, Chung Y, Lei J, Steenrod JM, Chen Q, Sajjan US, Hershenson MB (2014) Neonatal rhinovirus induces mucous metaplasia and airways hyperresponsiveness through IL-25 and type 2 innate lymphoid cells. J Allergy Clin Immunol 134:429–439

[23] Huang CK, Yang CY, Jeng YM, Chen CL, Wu HH, Chang YC, Ma C, Kuo WH, Chang KJ, Shew JY (2014) Autocrine/paracrine mechanism of interleukin-17B receptor promotes breast tumorigenesis through NF-kappaB-mediated antiapoptotic pathway. Oncogene 33:2968–2977

[24] Kaiko GE, Phipps S, Angkasekwinai P, Dong C, Foster PS (2010) NK cell deficiency predisposes to viral-induced Th2-type allergic inflammation via epithelial-derived IL-25. J Immunol 185:4681–4690

[25] Kitamura T, Qian BZ, Pollard JW (2015) Immune cell promotion of metastasis. Nat Rev Immunol 15:73–86

[26] Kohrt HE, Nouri N, Nowels K, Johnson D, Holmes S, Lee PP (2005) Profile of immune cells in axillary lymph nodes predicts diseasefree survival in breast cancer. PLoS Med 2:e284

[27] Licona-Limon P, Kim LK, Palm NW, Flavell RA (2013) TH2, allergy and group 2 innate lymphoid cells. Nat Immunol 14:536–542

[28] Lin EY, Nguyen AV, Russell RG, Pollard JW (2001) Colonystimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med 193:727–740

[29] Lin EY, Jones JG, Li P, Zhu UY, Whitney KD, Muller WJ, Pollard JW (2003) Progression to malignancy in the polyoma middle T oncoprotein mouse breast cancer model provides a reliable model for human diseases. Am J Pathol 163:2113–2126

[30] Lin SCJ, Lee KF, Nikitin AY, Hilsenbeck SG, Cardiff RD, Li AH, Kang KW, Frank SA, Lee WH, Lee EYHP (2004) Somatic mutation of p53 leads to estrogen receptor alpha-positive and –negative mouse mammary tumors with high frequency of metastasis. Cancer Res 64:3525–3532

[31] Lin EY, Li JF, Gnatovskiy L, Deng Y, Zhu L, Grzesik DA, Qian H, Xue XN, Pollard JW (2006) Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res 66:11238–11246

[32] Maglione JE, Moghanaki D, Young LJT, Manner CK, Ellies LG, Joseph SO, Nicholson B, Cardiff RD, MacLeod CL (2001) Transgenic Polyoma middle-T mice model premalignant mammary disease. Cancer Res 61:8298–8305

[33] Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454:436–444

[34] McCormack SJ, Weaver Z, Deming S, Natarajan G, Torri J, Johnson MD, Liyanage M, Ried T, Dickson RB (1998) Myc/p53 interactions in transgenic mouse mammary development, tumorigenesis and chromosomal instability. Oncogene 16:2755–2766

[35] Mombelli S, Cochaud S, Merrouche Y, Garbar C, Antonicelli F, Laprevotte E, Alberici G, Bonnefoy N, Eliaou JF, Bastid J (2015) IL-17A and its homologs IL-25/IL-17E recruit the c-RAF/S6 kinase pathway and the generation of pro-oncogenic LMW-E in breast cancer cells. Sci Rep 5:11874

[36] Moody SE, Sarkisian CJ, Hahn KT, Gunther EJ, Pickup S, Dugan KD, Innocent N, Cardiff RD, Schnall MD, Chodosh LA (2002) Conditional activation of Neu in the mammary epithelium of transgenic mice results in reversible pulmonary metastasis. Cancer Cell 2:451–461

[37] Nielsen LL, Discafani CM, Gurnani M, Tyler RD (1991) Histopathology of salivary and mammary-gland tumors in transgenic mice expressing a human Ha-ras oncogene. Cancer Res 51:3762–3767

[38] Noy R, Pollard JW (2014) Tumor-associated macrophages: from mechanisms to therapy. Immunity 41:49–61

[39] Pedroza-Gonzalez A, Xu K, Wu TC, Aspord C, Tindle S, Marches F, Gallegos M, Burton EC, Savino D, Hori T, Tanaka Y (2011) Thymic stromal lymphopoietin fosters human breast tumor growth by promoting type 2 inflammation. J Exp Med 208:479–490

[40] Prat A, Fan C, Fernandez A, Hoadley KA, Martinello R, Vidal M, Viladot M, Pineda E, Arance A, Munoz M (2015) Response and survival of breast cancer intrinsic subtypes following multiagent neoadjuvant chemotherapy. BMC Med 13:303

[41] Rizzo A, Monteleone I, Fina D, Stolfi C, Caruso R, Fantini MC, Franze E, Schwendener R, Pallone F, Monteleone G (2012) Inhibition of colitis by IL-25 associates with induction of alternatively activated macrophages. Inflamm Bowel Dis 18:449–459

[42] Siegle JS, Hansbro N, Dong C, Angkasekwinai P, Foster PS, Kumar RK (2011) Blocking induction of T helper type 2 responses prevents development of disease in a model of childhood asthma. Clin Exp Immunol 165:19–28

[43] Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98:10869–10874

[44] Stolfi C, Caruso R, Franze E, Sarra M, De Nitto D, Rizzo A, Pallone F, Monteleone G (2011) Interleukin-25 fails to activate STAT6 and induce alternatively activatedmacrophages. Immunology 132:66–77

[45] Swaidani S, Bulek K, Kang Z, Gulen MF, Liu C, Yin W, Abbadi A, Aronica M, Li X (2011) T cell-derived Act1 is necessary for IL-25-mediated Th2 responses and allergic airway inflammation. J Immunol 187:3155–3164

[46] Tsukamoto AS, Grosschedl R, Guzman RC, Parslow T, Varmus HE (1988) Expression of the int-1 gene in transgenic mice is associated with mammary-gland hyperplasia and adenocarcinomas in male and female mice. Cell 55:619–625

[47] Van Dyken SJ, Locksley RM (2013) Interleukin-4-and interleukin-13-mediated alternatively activated macrophages: roles in homeostasis and disease. Annual Review of Immunology 31(31):317–343

[48] Venkitaraman AR (2002) Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 108:171–182

[49] Wang YH, Angkasekwinai P, Lu N, Voo KS, Arima K, Hanabuchi S, Hippe A, Corrigan CJ, Dong C, Homey B (2007) IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC-activated Th2 memory cells. J Exp Med 204:1837–1847

[50] Wu HH, Hwang-Verslues WW, Lee WH, Huang CK, Wei PC, Chen CL, Shew JY, Lee EYHP, Jeng YM, Tien YW (2015) Targeting IL-17B-IL-17RB signaling with an anti-IL-17RB antibody blocks pancreatic cancer metastasis by silencing multiple chemokines. J Exp Med 212:333–349

[51] Zabuawala T, Taffany DA, Sharma SM, Merchant A, Adair B, Srinivasan R, Rosol TJ, Fernandez S, Huang K, Leone G (2010) An ets2-driven transcriptional program in tumor-associated macrophages promotes tumor metastasis. Cancer Res 70:1323–1333

RIGHTS & PERMISSIONS

2016 The Author(s) 2016. This article is published with open access at Springerlink.com and journal.hep.com.cn