B7-H4 expression in human infiltrating ductal carcinoma‑associated macrophages

Liu,Lei; Li,Dalin; Chen,Shuang; Zhao,Ran; Pang,Da; Li,Dianjun; Fu,Zhenkun

doi:10.3892/mmr.2016.5510

B7-H4 expression in human infiltrating ductal carcinoma‑associated macrophages

Authors:
- Lei Liu
- Dalin Li
- Shuang Chen
- Ran Zhao
- Da Pang
- Dianjun Li
- Zhenkun Fu
View Affiliations

Affiliations: Department of Immunology, Heilongjiang Provincial Key Laboratory for Infection and Immunity, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China, Department of Breast Surgery, The Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China, Department of Pathology, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
Published online on: July 13, 2016 https://doi.org/10.3892/mmr.2016.5510
Pages: 2135-2142

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

B7-H4 is a co‑inhibitory molecule of the B7 family, which is expressed on antigen‑presenting cells (APCs) and is able to limit the T‑cell immune response. Macrophages act as professional APCs and are important for immunoregulation of the tumor microenvironment in breast cancer. In order to identify the association between the presence of B7‑H4 on macrophages and infiltrating ductal carcinoma (IDC), the present study investigated the expression of B7‑H4 on macrophages with different polarizations. The expression levels of B7‑H4 in IDC tissues were determined using immunohistochemistry, and the expression of B7‑H4 on macrophages in the breast IDC microenvironment were determined using western blot analysis and reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). The expression levels of interleukin (IL)‑6 and IL‑10 were detected in IDC tissues and the supernatants of polarized macrophages using an enzyme‑linked immunosorbent assay and RT‑qPCR. The present study demonstrated that B7‑H4 was overexpressed in IDC tissues and macrophages. In vitro, M1 and M2 macrophages exhibited different expression levels of B7‑H4. IL‑6 and ‑10 exhibited higher expression in the IDC tissues compared with in distal pericarcinomatous tissues. In conclusion, B7‑H4 exhibited overexpression in IDC tissues and cultured macrophage cells. Furthermore, M2 macrophages exhibited higher expression levels of B7‑H4 compared with the M1 subtype. In addition, IL‑6 and ‑10 may be associated with B7‑H4 expression on macrophages of different polarizations in the IDC microenvironment.

View Figures

View References

1	Evans AJ, Pinder SE, Snead DR, Wilson AR, Ellis IO and Elston CW: The detection of ductal carcinoma in situ at mammographic screening enables the diagnosis of small, grade 3 invasive tumours. Br J Cancer. 75:542–544. 1997. View Article : Google Scholar : PubMed/NCBI
2	Standish LJ, Sweet ES, Novack J, Wenner CA, Bridge C, Nelson A, Martzen M and Torkelson C: Breast cancer and the immune system. J Soc Integr Oncol. 6:158–168. 2008.
3	Watanabe MA, Oda JM, Amarante MK and Cesar Voltarelli J: Regulatory T cells and breast cancer: Implications for immunopathogenesis. Cancer Metastasis Rev. 29:569–579. 2010. View Article : Google Scholar : PubMed/NCBI
4	Grieco V, Rondena M, Romussi S, Stefanello D and Finazzi M: Immunohistochemical characterization of the leucocytic infiltrate associated with canine seminomas. J Comp Pathol. 130:278–284. 2004. View Article : Google Scholar : PubMed/NCBI
5	Carvalho MI, Pires I, Prada J and Queiroga FL: A role for T-lymphocytes in human breast cancer and in canine mammary tumors. Biomed Res Int. 2014:1308942014. View Article : Google Scholar : PubMed/NCBI
6	Gordon S and Taylor PR: Monocyte and macrophage heterogeneity. Nat Rev Immunol. 5:953–964. 2005. View Article : Google Scholar : PubMed/NCBI
7	Mantovani A, Sozzani S, Locati M, Allavena P and Sica A: Macrophage polarization: Tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 23:549–555. 2002. View Article : Google Scholar : PubMed/NCBI
8	Sica A and Bronte V: Altered macrophage differentiation and immune dysfunction in tumor development. J Clin Invest. 117:1155–1166. 2007. View Article : Google Scholar : PubMed/NCBI
9	Biswas SK, Sica A and Lewis CE: Plasticity of macrophage function during tumor progression: Regulation by distinct molecular mechanisms. J Immunol. 180:2011–2017. 2008. View Article : Google Scholar : PubMed/NCBI
10	Qian ZB and Pollard JW: Macrophage diversity enhances tumor progression and metastasis. Cell. 141:39–51. 2010. View Article : Google Scholar : PubMed/NCBI
11	Sica GL, Choi IH, Zhu G, Tamada K, Wang SD, Tamura H, Chapoval AI, Flies DB, Bajorath J and Chen L: B7-H4, a molecule of the B7 family, negatively regulates T cell immunity. Immunity. 18:849–861. 2003. View Article : Google Scholar : PubMed/NCBI
12	Zang X, Loke P, Kim J, Murphy K, Waitz R and Allison JP: B7x: A widely expressed B7 family member that inhibits T cell activation. Proc Natl Acad Sci USA. 100:10388–10392. 2003. View Article : Google Scholar : PubMed/NCBI
13	Biswas SK and Mantovani A: Macrophage plasticity and interaction with lymphocyte subsets: Cancer as a paradigm. Nat Immunol. 11:889–896. 2010. View Article : Google Scholar : PubMed/NCBI
14	Maitra A, Ashfaq R, Gunn CR, Rahman A, Yeo CJ, Sohn TA, Cameron JL, Hruban RH and Wilentz RE: Cyclooxygenase 2 expression in pancreatic adenocarcinoma and pancreatic intraepithelial neoplasia: An immunohistochemical analysis with automated cellular imaging. Am J Clin Pathol. 118:194–201. 2002. View Article : Google Scholar : PubMed/NCBI
15	Kumar M and Nandi S: Development of a SYBR Green based real-time PCR assay for detection and quantitation of canine parvovirus in faecal samples. J Virol Methods. 169:198–201. 2010. View Article : Google Scholar : PubMed/NCBI
16	Kabayiza JC, Andersson ME, Welinder-Olsson C, Bergström T, Muhirwa G and Lindh M: Comparison of rectal swabs and faeces for real-time PCR detection of enteric agents in Rwandan children with gastroenteritis. BMC Infect Dis. 13:4472013. View Article : Google Scholar : PubMed/NCBI
17	Cheng J, Huo DH, Kuang DM, Yang J, Zheng L and Zhuang SM: Human macrophages promote the motility and invasiveness of osteopontin-knockdown tumor cells. Cancer Res. 67:5141–5147. 2007. View Article : Google Scholar : PubMed/NCBI
18	Gocheva V, Wang HW, Gadea BB, Shree T, Hunter KE, Garfall AL, Berman T and Joyce JA: IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion. Genes Dev. 24:241–255. 2010. View Article : Google Scholar : PubMed/NCBI
19	Yang J, Zhang Z, Chen C, Liu Y, Si Q, Chuang TH, Li N, Gomez-Cabrero A, Reisfeld RA, Xiang R and Luo Y: MicroRNA-19a-3p inhibits breast cancer progression and metastasis by inducing macrophage polarization through downregulated expression of Fra-1 proto-oncogene. Oncogene. 33:3014–3023. 2014. View Article : Google Scholar
20	Jang JY, Lee JK, Jeon YK and Kim CW: Exosome derived from epigallocatechin gallate treated breast cancer cells suppresses tumor growth by inhibiting tumor-associated macrophage infiltration and M2 polarization. BMC Cancer. 13:4212013. View Article : Google Scholar : PubMed/NCBI
21	Oghumu S, Varikuti S, Terrazas C, Kotov D, Nasser MW, Powell CA, Ganju RK and Satoskar AR: CXCR3 deficiency enhances tumor progression by promoting macrophage M2 polarization in a murine breast cancer model. Immunology. 143:109–119. 2014. View Article : Google Scholar : PubMed/NCBI
22	Jia X, Yu F, Wang J, Iwanowycz S, Saaoud F, Wang Y, Hu J, Wang Q and Fan D: Emodin suppresses pulmonary metastasis of breast cancer accompanied with decreasedmacrophage recruitment and M2 polarization in the lungs. Breast Cancer Res Treat. 148:291–302. 2014. View Article : Google Scholar : PubMed/NCBI
23	Mills CD, Kincaid K, Alt JM, Heilman MJ and Hill AM: M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol. 164:6166–6173. 2000. View Article : Google Scholar : PubMed/NCBI
24	Kryczek I, Zou L, Rodriguez P, Zhu G, Wei S, Mottram P, Brumlik M, Cheng P, Curiel T, Myers L, et al: B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. J Exp Med. 203:871–881. 2006. View Article : Google Scholar : PubMed/NCBI
25	Chen C, Zhu YB, Shen Y, Zhu YH, Zhang XG and Huang JA: Increase of circulating B7-H4-expressing CD68+ macrophage correlated with clinical stage of lung carcinomas. J Immunother. 35:354–358. 2012. View Article : Google Scholar : PubMed/NCBI
26	Salceda S, Tang T, Kmet M, Munteanu A, Ghosh M, Macina R, Liu W, Pilkington G and Papkoff J: The immunomodulatory protein B7-H4 is overexpressed in breast and ovarian cancers and promotes epithelial cell transformation. Exp Cell Res. 306:128–141. 2005. View Article : Google Scholar : PubMed/NCBI
27	Tringler B, Zhuo S, Pilkington G, Torkko KC, Singh M, Lucia MS, Heinz DE, Papkoff J and Shroyer KR: B7-h4 is highly expressed in ductal and lobular breast cancer. Clin Cancer Res. 11:1842–1848. 2005. View Article : Google Scholar : PubMed/NCBI
28	Mugler KC, Singh M, Tringler B, Torkko KC, Liu W, Papkoff J and Shroyer KR: B7-h4 expression in a range of breast pathology: Correlation with tumor T-cell infiltration. Appl Immunohistochem Mol Morphol. 15:363–370. 2007. View Article : Google Scholar : PubMed/NCBI
29	Raes G, Brys L, Dahal BK, Brandt J, Grooten J, Brombacher F, Vanham G, Noël W, Bogaert P, Boonefaes T, et al: Macrophage galactose-type C-type lectins as novel markers for alternatively activated macrophages elicited by parasitic infections and allergic airway inflammation. J Leukoc Biol. 77:321–327. 2005. View Article : Google Scholar
30	Loke P, Nair MG, Parkinson J, Guiliano D, Blaxter M and Allen JE: IL-4 dependent alternatively-activated macrophages have a distinctive in vivo gene expression phenotype. BMC Immunol. 3:72002. View Article : Google Scholar : PubMed/NCBI
31	Wang L, Yi T, Kortylewski M, Pardoll DM, Zeng D and Yu H: IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway. J Exp Med. 206:1457–1464. 2009. View Article : Google Scholar : PubMed/NCBI
32	Kortylewski M, Kujawski M, Wang T, Wei S, Zhang S, Pilon-Thomas S, Niu G, Kay H, Mulé J, Kerr WG, et al: Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med. 11:1314–1321. 2005. View Article : Google Scholar : PubMed/NCBI
33	Chen L: Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol. 4:336–347. 2004. View Article : Google Scholar : PubMed/NCBI
34	Smith JB, Stashwick C and Powell DJ Jr: B7-H4 as a potential target for immunotherapy for gynecologic cancers: A closer look. Gynecol Oncol. 134:181–189. 2014. View Article : Google Scholar : PubMed/NCBI