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On-line Access: 2014-01-04

Received: 2013-10-20

Revision Accepted: 2013-12-01

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Journal of Zhejiang University SCIENCE B 2014 Vol.15 No.1 P.1-15


Harnessing the immune system for the treatment of breast cancer

Author(s):  Xinguo Jiang

Affiliation(s):  . Department of Medicine, VA Palo Alto Health Care System/Stanford University School of Medicine, Stanford, CA 94305, USA

Corresponding email(s):   xinguoj@stanford.edu

Key Words:  Breast cancer, Chronic inflammation, Protumorigenic immune cells, Therapeutic vaccines, Immunotherapy

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Xinguo Jiang. Harnessing the immune system for the treatment of breast cancer[J]. Journal of Zhejiang University Science B, 2014, 15(1): 1-15.

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Standard treatment options for breast cancer include surgery, chemotherapy, radiation, and targeted therapies, such as adjuvant hormonal therapy and monoclonal antibodies. Recently, the recognition that chronic inflammation in the tumor microenvironment promotes tumor growth and survival during different stages of breast cancer development has led to the development of novel immunotherapies. Several immunotherapeutic strategies have been studied both preclinically and clinically and already have been shown to enhance the efficacy of conventional treatment modalities. Therefore, therapies targeting the immune system may represent a promising next-generation approach for the treatment of breast cancers. This review will discuss recent findings that elucidate the roles of suppressive immune cells and proinflammatory cytokines and chemokines in the tumor-promoting microenvironment, and the most current immunotherapeutic strategies in breast cancer.




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[1] Aceto, N., Duss, S., Macdonald, G., 2012. Co-expression of HER2 and HER3 receptor tyrosine kinases enhances invasion of breast cells via stimulation of interleukin-8 autocrine secretion. Breast Cancer Res, 14(5):R131

[2] Acharyya, S., Oskarsson, T., Vanharanta, S., 2012. A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell, 150(1):165-178. 

[3] Basu, S., Nachat-Kappes, R., Caldefie-Chezet, F., 2013. Eicosanoids and adipokines in breast cancer: from molecular mechanisms to clinical considerations. Antioxid Redox Signal, 18(3):323-360. 

[4] Bates, G.J., Fox, S.B., Han, C., 2006. Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol, 24(34):5373-5380. 

[5] Baumgarten, S.C., Frasor, J., 2012. Minireview: Inflammation: an instigator of more aggressive estrogen receptor (ER) positive breast cancers. Mol Endocrinol, 26(3):360-371. 

[6] Ben-Baruch, A., 2003. Host microenvironment in breast cancer development: inflammatory cells, cytokines and chemokines in breast cancer progression: reciprocal tumor-microenvironment interactions. Breast Cancer Res, 5(1):31-36. 

[7] Benevides, L., Cardoso, C.R., Tiezzi, D.G., 2013. Enrichment of regulatory T cells in invasive breast tumor correlates with the upregulation of IL-17A expression and invasiveness of the tumor. Eur J Immunol, 43(6):1518-1528. 

[8] Biswas, S.K., Mantovani, A., 2010. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol, 11(10):889-896. 

[9] Bohling, S.D., Allison, K.H., 2008. Immunosuppressive regulatory T cells are associated with aggressive breast cancer phenotypes: a potential therapeutic target. Mod Pathol, 21:1527-1532. 

[10] Boimel, P.J., Smirnova, T., Zhou, Z.N., 2012. Contribution of CXCL12 secretion to invasion of breast cancer cells. Breast Cancer Res, 14(1):R23

[11] Brahmer, J.R., Tykodi, S.S., Chow, L.Q., 2012. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med, 366:2455-2465. 

[12] Bray, F., Jemal, A., Grey, N., 2012. Global cancer transitions according to the Human Development Index (2008‒2030): a population-based study. Lancet Oncol, 13(8):790-801. 

[13] Britschgi, A., Andraos, R., Brinkhaus, H., 2012. JAK2/STAT5 inhibition circumvents resistance to PI3K/mTOR blockade: a rationale for cotargeting these pathways in metastatic breast cancer. Cancer Cell, 22(6):796-811. 

[14] Campbell, M.J., Tonlaar, N.Y., Garwood, E.R., 2011. Proliferating macrophages associated with high grade, hormone receptor negative breast cancer and poor clinical outcome. Breast Cancer Res Treat, 128(3):703-711. 

[15] Ceran, C., Cokol, M., Cingoz, S., 2012. Novel anti-HER2 monoclonal antibodies: synergy and antagonism with tumor necrosis factor-α. BMC Cancer, 12(1):450

[16] Charafe-Jauffret, E., Ginestier, C., Iovino, F., 2009. Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Res, 69(14):1302-1313. 

[17] Chaturvedi, P., Gilkes, D.M., Wong, C.C., 2013. Hypoxia-inducible factor-dependent breast cancer-mesenchymal stem cell bidirectional signaling promotes metastasis. J Clin Invest, 123:189-205. 

[18] Chen, E.P., Smyth, E.M., 2011. COX-2 and PGE2-dependent immunomodulation in breast cancer. Prostaglandins Other Lipid Mediat, 96(1-4):14-20. 

[19] Chen, Q., Zhang, X.H., Massague, J., 2011. Macrophage binding to receptor VCAM-1 transmits survival signals in breast cancer cells that invade the lungs. Cancer Cell, 20(4):538-549. 

[20] Chen, W.C., Lai, Y.H., Chen, H.Y., 2013. Interleukin-17-producing cell infiltration in the breast cancer tumour microenvironment is a poor prognostic factor. Histopathology, 63(2):225-233. 

[21] Coussens, L.M., Pollard, J.W., 2011. Leukocytes in mammary development and cancer. Cold Spring Harb Perspect Biol, 3(3):a003285

[22] Coussens, L.M., Zitvogel, L., Palucka, A.K., 2013. Neutralizing tumor-promoting chronic inflammation: a magic bullet. Science, 339(6117):286-291. 

[23] Dalotto-Moreno, T., Croci, D.O., Cerliani, J.P., 2013. Targeting galectin-1 overcomes breast cancer-associated immunosuppression and prevents metastatic disease. Cancer Res, 73(3):1107-1117. 

[24] DeNardo, D.G., Coussens, L.M., 2007. Inflammation and breast cancer. Balancing immune response: crosstalk between adaptive and innate immune cells during breast cancer progression. Breast Cancer Res, 9(4):212

[25] DeNardo, D.G., Brennan, D.J., Rexhepaj, E., 2011. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov, 1(1):54-67. 

[26] de Palma, M., Lewis, C.E., 2013. Macrophage regulation of tumor responses to anticancer therapies. Cancer Cell, 23(3):277-286. 

[27] Dethlefsen, C., Hojfeldt, G., Hojman, P., 2013. The role of intratumoral and systemic IL-6 in breast cancer. Breast Cancer Res Treat, 138(3):657-664. 

[28] Dewan, M.Z., Galloway, A.E., Kawashima, N., 2009. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res, 15(17):5379-5388. 

[29] Diaz-Montero, C.M., Salem, M.L., Nishimura, M.I., 2009. Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother, 58(1):49-59. 

[30] Ding, J., Jin, W., Chen, C., 2012. Tumor associated macrophage×cancer cell hybrids may acquire cancer stem cell properties in breast cancer. PLoS ONE, 7(7):e41942

[31] Dirkx, A.E., Oude Egbrink, M.G.A., Wagstaff, J., 2006. Monocyte/macrophage infiltration in tumors: modulators of angiogenesis. J Leukoc Biol, 80(3):1183-1196. 

[32] Disis, M.L., Wallace, D.R., Gooley, T.A., 2009. Concurrent trastuzumab and HER2/neu-specific vaccination in patients with metastatic breast cancer. J Clin Oncol, 27(28):4685-4692. 

[33] Dong, C., 2006. Diversification of T-helper-cell lineages: finding the family root of IL-17-producing cells. Nat Rev Immunol, 6(4):329-333. 

[34] Emens, L.A., 2012. Breast cancer immunobiology driving immunotherapy: vaccines and immune checkpoint blockade. Expert Rev Anticancer Ther, 12(12):1597-1611. 

[35] Finak, G., Bertos, N., Pepin, F., 2008. Stromal gene expression predicts clinical outcome in breast cancer. Nat Med, 14(5):518-527. 

[36] Gabrilovich, D.I., Nagaraj, S., 2009. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol, 9(3):162-174. 

[37] Gabrilovich, D.I., Ostrand-Rosenberg, S., Bronte, V., 2012. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol, 12:253-268. 

[38] Gautier, E.L., Shay, T., Miller, J., 2012. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat Immunol, 13:1118-1128. 

[39] Ge, Y., Xi, H., Ju, S., 2013. Blockade of PD-1/PD-L1 immune checkpoint during DC vaccination induces potent protective immunity against breast cancer in hu-SCID mice. Cancer Lett, 336(2):253-259. 

[40] Gil, M., Seshadri, M., Komorowski, M.P., 2013. Targeting CXCL12/CXCR4 signaling with oncolytic virotherapy disrupts tumor vasculature and inhibits breast cancer metastases. PNAS, 110(14):E1291-E1300. 

[41] Gobert, M., Treilleux, I., Bendriss-Vermare, N., 2009. Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancer Res, 69(5):2000-2009. 

[42] Goldberg, J.E., Schwertfeger, K.L., 2010. Proinflammatory cytokines in breast cancer: mechanisms of action and potential targets for therapeutics. Curr Drug Targets, 11(9):1133-1146. 

[43] Greenwald, R.J., Freeman, G.J., Sharpe, A.H., 2005. The B7 family revisited. Annu Rev Immunol, 23(1):515-548. 

[44] Groh, V., Wu, J., Yee, C., 2002. Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature, 419(6908):734-738. 

[45] Hamidullah, ., Changkija, B., Konwar, R., 2012. Role of interleukin-10 in breast cancer. Breast Cancer Res Treat, 133(1):11-21. 

[46] Hanahan, D., Weinberg, R.A., 2011. Hallmarks of cancer: the next generation. Cell, 144(5):646-674. 

[47] Hanks, B.A., Holtzhausen, A., Evans, K.S., 2013. Type III TGF-β receptor downregulation generates an immunotolerant tumor microenvironment. J Clin Invest, 123(9):3925-3940. 

[48] Harrington, L.E., Hatton, R.D., Mangan, P.R., 2005. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol, 6:1123-1132. 

[49] Hartman, Z.C., Poage, G.M., den Hollander, P., 2013. Growth of triple-negative breast cancer cells relies upon coordinate autocrine expression of the proinflammatory cytokines IL-6 and IL-8. Cancer Res, 73(11):3470-3480. 

[50] Huang, B., Pan, P.Y., Li, Q., 2006. Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host. Cancer Res, 66(2):1123-1131. 

[51] Huang, Y., Yuan, J., Righi, E., 2012. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. PNAS, 109(43):17561-17566. 

[52] Hwang, M.S., Yu, N., Stinson, S.Y., 2013. miR-221/222 targets adiponectin receptor 1 to promote the epithelial-to-mesenchymal transition in breast cancer. PLoS ONE, 8(6):e66502

[53] Ibrahim, N.K., Murray, J.L., Zhou, D., 2013. Survival advantage in patients with metastatic breast cancer receiving endocrine therapy plus sialyl Tn-KLH vaccine: post hoc analysis of a large randomized trial. J Cancer, 4(7):577-584. 

[54] Iliopoulos, D., Hirsch, H.A., Struhl, K., 2009. An epigenetic switch involving NF-κB, Lin28, Let-7 microRNA, and IL6 links inflammation to cell transformation. Cell, 139(4):693-706. 

[55] Ishihara, D., Dovas, A., Hernandez, L., 2013. Wiskott-Aldrich syndrome protein regulates leukocyte-dependent breast cancer metastasis. Cell Rep, 4(3):429-436. 

[56] Jemal, A., Center, M.M., DeSantis, C., 2010. Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomarkers Prev, 19(8):1893-1907. 

[57] Jiang, X., Shapiro, D.J., 2014. The immune system and inflammation in breast cancer. Mol Cell Endocrinol, 382(1):673-682. 

[58] Jiang, X., Orr, B.A., Kranz, D.M., 2006. Estrogen induction of the granzyme B inhibitor, proteinase inhibitor 9, protects cells against apoptosis mediated by cytotoxic T lymphocytes and natural killer cells. Endocrinology, 147(3):1419-1426. 

[59] Jiang, X., Ellison, S.J., Alarid, E.T., 2007. Interplay between the levels of estrogen and estrogen receptor controls the level of the granzyme inhibitor, proteinase inhibitor 9 and susceptibility to immune surveillance by natural killer cells. Oncogene, 26:4106-4114. 

[60] Jiang, X., Patterson, N.M., Ling, Y., 2008. Low concentrations of the soy phytoestrogen genistein induce proteinase inhibitor 9 and block killing of breast cancer cells by immune cells. Endocrinology, 149(11):5366-5373. 

[61] Joffroy, C.M., Buck, M.B., Stope, M.B., 2010. Antiestrogens induce transforming growth factor β-mediated immunosuppression in breast cancer. Cancer Res, 70(4):1314-1322. 

[62] Kakarala, M., Wicha, M.S., 2008. Implications of the cancer stem-cell hypothesis for breast cancer prevention and therapy. J Clin Oncol, 26(17):2813-2820. 

[63] Karavitis, J., Hix, L.M., Shi, Y.H., 2012. Regulation of COX2 expression in mouse mammary tumor cells controls bone metastasis and PGE2-induction of regulatory T cell migration. PLoS ONE, 7(9):e46342

[64] Kim, H., Choi, J.A., Park, G.S., 2012. BLT2 up-regulates interleukin-8 production and promotes the invasiveness of breast cancer cells. PLoS ONE, 7(11):e49186

[65] Korkaya, H., Liu, S., Wicha, M.S., 2011. Breast cancer stem cells, cytokine networks, and the tumor microenvironment. J Clin Invest, 121(10):3804-3809. 

[66] Korkaya, H., Kim, G.I., Davis, A., 2012. Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2+ breast cancer by expanding the cancer stem cell population. Mol Cell, 47(4):570-584. 

[67] Korn, T., Bettelli, E., Oukka, M., 2009. IL-17 and Th17 cells. Annu Rev Immunol, 27(1):485-517. 

[68] Laoui, D., Movahedi, K., van Overmeire, E., 2011. Tumor-associated macrophages in breast cancer: distinct subsets, distinct functions. Int J Dev Biol, 55(7-8-9):861-867. 

[69] Leek, R.D., Lewis, C.E., Whitehouse, R., 1996. Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res, 56(20):4625-4629. 

[70] Leek, R.D., Hunt, N.C., Landers, R.J., 2000. Macrophage infiltration is associated with VEGF and EGFR expression in breast cancer. J Pathol, 190(4):430-436. 

[71] Lewis, J.S., Landers, R.J., Underwood, J.C., 2000. Expression of vascular endothelial growth factor by macrophages is up-regulated in poorly vascularized areas of breast carcinomas. J Pathol, 192(2):150-158. 

[72] Li, C.W., Xia, W., Huo, L., 2012. Epithelial-mesenchymal transition induced by TNF-α requires NF-κB-mediated transcriptional upregulation of Twist1. Cancer Res, 72(5):1290-1300. 

[73] Li, J., Zhang, B.N., Fan, J.H., 2011. A nation-wide multicenter 10-year (1999–2008) retrospective clinical epidemiological study of female breast cancer in China. BMC Cancer, 11(1):364

[74] Li, S., Kendall, S.E., Raices, R., 2012. TWIST1 associates with NF-κB subunit RELA via carboxyl-terminal WR domain to promote cell autonomous invasion through IL8 production. BMC Biol, 10(1):73

[75] Liu, Y., Lai, L., Chen, Q., 2012. MicroRNA-494 is required for the accumulation and functions of tumor-expanded myeloid-derived suppressor cells via targeting of PTEN. J Immunol, 188(11):5500-5510. 

[76] Lu, T., Ramakrishnan, R., Altiok, S., 2011. Tumor-infiltrating myeloid cells induce tumor cell resistance to cytotoxic T cells in mice. J Clin Invest, 121(10):4015-4029. 

[77] Mahmoud, S.M., Paish, E.C., Powe, D.G., 2011. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin Oncol, 29(15):1949-1955. 

[78] Mahmoud, S.M., Lee, A.H., Paish, E.C., 2012. Tumour-infiltrating macrophages and clinical outcome in breast cancer. J Clin Pathol, 65(2):159-163. 

[79] Mantovani, A., Allavena, P., Sica, A., 2008. Cancer-related inflammation. Nature, 454(7203):436-444. 

[80] Mao, H., Zhang, L., Yang, Y., 2010. New insights of CTLA-4 into its biological function in breast cancer. Curr Cancer Drug Targets, 10(7):728-736. 

[81] Markosyan, N., Chen, E.P., Evans, R.A., 2013. Mammary carcinoma cell derived cyclooxygenase 2 suppresses tumor immune surveillance by enhancing intratumoral immune checkpoint activity. Breast Cancer Res, 15(5):R75

[82] Markowitz, J., Wesolowski, R., Papenfuss, T., 2013. Myeloid-derived suppressor cells in breast cancer. Breast Cancer Res Treat, 140(1):13-21. 

[83] Marotta, L.L., Almendro, V., Marusyk, A., 2011. The JAK2/STAT3 signaling pathway is required for growth of CD44+CD24 stem cell-like breast cancer cells in human tumors. J Clin Invest, 121(7):2723-2735. 

[84] Mauti, L.A., Le Bitoux, M.A., Baumer, K., 2011. Myeloid-derived suppressor cells are implicated in regulating permissiveness for tumor metastasis during mouse gestation. J Clin Invest, 121(7):2794-2807. 

[85] Miles, D., Roche, H., Martin, M., 2011. Phase III multicenter clinical trial of the sialyl-TN (STn)-keyhole limpet hemocyanin (KLH) vaccine for metastatic breast cancer. Oncologist, 16(8):1092-1100. 

[86] Mohebtash, M., Tsang, K.Y., Madan, R.A., 2011. A pilot study of MUC-1/CEA/TRICOM poxviral-based vaccine in patients with metastatic breast and ovarian cancer. Clin Cancer Res, 17(22):7164-7173. 

[87] Montero, A.J., Diaz-Montero, C.M., Deutsch, Y.E., 2012. Phase 2 study of neoadjuvant treatment with NOV-002 in combination with doxorubicin and cyclophosphamide followed by docetaxel in patients with HER-2 negative clinical stage II‒IIIc breast cancer. Breast Cancer Res Treat, 132(1):215-223. 

[88] Morales, J.K., Kmieciak, M., Graham, L., 2009. Adoptive transfer of HER2/neu-specific T cells expanded with alternating gamma chain cytokines mediate tumor regression when combined with the depletion of myeloid-derived suppressor cells. Cancer Immunol Immunother, 58(6):941-953. 

[89] Muenst, S., Soysal, S.D., Gao, F., 2013. The presence of programmed death 1 (PD-1)-positive tumor-infiltrating lymphocytes is associated with poor prognosis in human breast cancer. Breast Cancer Res Treat, 139(3):667-676. 

[90] Mukherjee, D., Zhao, J., 2013. The role of chemokine receptor CXCR4 in breast cancer metastasis. Am J Cancer Res, 3(1):46-57. 

[91] Muller, A.J., DuHadaway, J.B., Donover, P.S., 2005. Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nat Med, 11(3):312-319. 

[92] Murray, P.J., Wynn, T.A., 2011. Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol, 11(11):723-737. 

[93] Na, Y.R., Yoon, Y.N., Son, D.I., 2013. Cyclooxygenase-2 inhibition blocks M2 macrophage differentiation and suppresses metastasis in murine breast cancer model. PLoS ONE, 8(5):e63451

[94] Nagaraj, S., Gupta, K., Pisarev, V., 2007. Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. Nat Med, 13(7):828-835. 

[95] Novitskiy, S.V., Pickup, M.W., Gorska, A.E., 2011. TGF-β receptor II loss promotes mammary carcinoma progression by Th17-dependent mechanisms. Cancer Discov, 1(5):430-441. 

[96] Obeid, E., Nanda, R., Fu, Y.X., 2013. The role of tumor-associated macrophages in breast cancer progression (review). Int J Oncol, 43(1):5-12. 

[97] Ohara, M., Yamaguchi, Y., Matsuura, K., 2009. Possible involvement of regulatory T cells in tumor onset and progression in primary breast cancer. Cancer Immunol Immunother, 58(3):441-447. 

[98] Olkhanud, P.B., Damdinsuren, B., Bodogai, M., 2011. Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4+ T cells to T-regulatory cells. Cancer Res, 71(10):3505-3515. 

[99] Osborne, C.K., Schiff, R., 2011. Mechanisms of endocrine resistance in breast cancer. Annu Rev Med, 62(1):233-247. 

[100] O'Sullivan, C., Lewis, C.E., Harris, A.L., 1993. Secretion of epidermal growth factor by macrophages associated with breast carcinoma. Lancet, 342(8864):148-149. 

[101] Pardoll, D.M., 2012. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer, 12(4):252-264. 

[102] Pfannenstiel, L.W., Lam, S.S., Emens, L.A., 2010. Paclitaxel enhances early dendritic cell maturation and function through TLR4 signaling in mice. Cell Immunol, 263(1):79-87. 

[103] Pruitt, S.K., Boczkowski, D., de Rosa, N., 2011. Enhancement of anti-tumor immunity through local modulation of CTLA-4 and GITR by dendritic cells. Eur J Immunol, 41(12):3553-3563. 

[104] Qian, B.Z., Pollard, J.W., 2010. Macrophage diversity enhances tumor progression and metastasis. Cell, 141(1):39-51. 

[105] Qian, X., Gu, L., Ning, H., 2013. Increased Th17 cells in the tumor microenvironment is mediated by IL-23 via tumor-secreted prostaglandin E2J Immunol, 190(11):5894-5902. 

[106] Rech, A.J., Mick, R., Martin, S., 2012. CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients. Sci Transl Med, 4(134):134ra62

[107] Ribatti, D., Nico, B., Crivellato, E., 2007. Macrophages and tumor angiogenesis. Leukemia, 21:2085-2089. 

[108] Rokavec, M., Wu, W., Luo, J.L., 2012. IL6-mediated suppression of miR-200c directs constitutive activation of inflammatory signaling circuit driving transformation and tumorigenesis. Mol Cell, 45(6):777-789. 

[109] Ruffell, B., Affara, N.I., Coussens, L.M., 2012. Differential macrophage programming in the tumor microenvironment. Trends Immunol, 33(3):119-126. 

[110] Ryan, B.M., Konecny, G.E., Kahlert, S., 2006. Survivin expression in breast cancer predicts clinical outcome and is associated with HER2, VEGF, urokinase plasminogen activator and PAI-1. Ann Oncol, 17(4):597-604. 

[111] Sakaguchi, S., Miyara, M., Costantino, C.M., 2010. FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol, 10(7):490-500. 

[112] Salgado, R., Junius, S., Benoy, I., 2003. Circulating interleukin-6 predicts survival in patients with metastatic breast cancer. Int J Cancer, 103(5):642-646. 

[113] Schlom, J., 2012. Therapeutic cancer vaccines: current status and moving forward. J Natl Cancer Inst, 104(8):599-613. 

[114] Schreiber, R.D., Old, L.J., Smyth, M.J., 2011. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science, 331(6024):1565-1570. 

[115] Shevach, E.M., 2009. Mechanisms of Foxp3+ T regulatory cell-mediated suppression. Immunity, 30(5):636-645. 

[116] Shin, M.S., Kim, H.S., Lee, S.H., 2001. Mutations of tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1) and receptor 2 (TRAIL-R2) genes in metastatic breast cancers. Cancer Res, 61:4942-4946. 

[117] Singh, J.K., Farnie, G., Bundred, N.J., 2013. Targeting CXCR1/2 significantly reduces breast cancer stem cell activity and increases the efficacy of inhibiting HER2 via HER2-dependent and -independent mechanisms. Clin Cancer Res, 19(3):643-656. 

[118] Sinha, P., Clements, V.K., Ostrand-Rosenberg, S., 2005. Interleukin-13-regulated M2 macrophages in combination with myeloid suppressor cells block immune surveillance against metastasis. Cancer Res, 65(24):11743-11751. 

[119] Sisirak, V., Faget, J., Gobert, M., 2012. Impaired IFN-α production by plasmacytoid dendritic cells favors regulatory T-cell expansion that may contribute to breast cancer progression. Cancer Res, 72(20):5188-5197. 

[120] Spranger, S., Spaapen, R.M., Zha, Y., 2013. Up-regulation of PD-L1, IDO, and Tregs in the melanoma tumor microenvironment is driven by CD8+ T cells. Sci Transl Med, 5(200):200ra116

[121] Stagg, J., Allard, B., 2013. Immunotherapeutic approaches in triple-negative breast cancer: latest research and clinical prospects. Ther Adv Med Oncol, 5(3):169-181. 

[122] Stagg, J., Loi, S., Divisekera, U., 2011. Anti-ErbB-2 mAb therapy requires type I and II interferons and synergizes with anti-PD-1 or anti-CD137 mAb therapy. PNAS, 108(17):7142-7147. 

[123] Steding, C.E., Wu, S.T., Zhang, Y., 2011. The role of interleukin-12 on modulating myeloid-derived suppressor cells, increasing overall survival and reducing metastasis. Immunology, 133(2):221-238. 

[124] Tan, W., Zhang, W., Strasner, A., 2011. Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature, 470(7335):548-553. 

[125] Tang, X., 2013. Tumor-associated macrophages as potential diagnostic and prognostic biomarkers in breast cancer. Cancer Lett, 332(1):3-10. 

[126] Thakur, A., Schalk, D., Sarkar, S.H., 2012. A Th1 cytokine-enriched microenvironment enhances tumor killing by activated T cells armed with bispecific antibodies and inhibits the development of myeloid-derived suppressor cells. Cancer Immunol Immunother, 61(4):497-509. 

[127] Todorović-Raković, N., Milovanović, J., 2013. Interleukin-8 in breast cancer progression. J Interferon Cytokine Res, 33(10):563-570. 

[128] Tsutsui, S., Yasuda, K., Suzuki, K., 2005. Macrophage infiltration and its prognostic implications in breast cancer: the relationship with VEGF expression and microvessel density. Oncol Rep, 14(2):425-431. 

[129] Uyttenhove, C., Pilotte, L., Theate, I., 2003. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med, 9:1269-1274. 

[130] Verbrugge, I., Hagekyriakou, J., Sharp, L.L., 2012. Radiotherapy increases the permissiveness of established mammary tumors to rejection by immunomodulatory antibodies. Cancer Res, 72(13):3163-3174. 

[131] Vesely, M.D., Kershaw, M.H., Schreiber, R.D., 2011. Natural innate and adaptive immunity to cancer. Annu Rev Immunol, 29(1):235-271. 

[132] von Mehren, M., Arlen, P., Tsang, K.Y., 2000. Pilot study of a dual gene recombinant avipox vaccine containing both carcinoembryonic antigen (CEA) and B7.1 transgenes in patients with recurrent CEA-expressing adenocarcinomas. Clin Cancer Res, 6(6):2219-2228. 

[133] von Mehren, M., Arlen, P., Gulley, J., 2001. The influence of granulocyte macrophage colony-stimulating factor and prior chemotherapy on the immunological response to a vaccine (ALVAC-CEA B7.1) in patients with metastatic carcinoma. Clin Cancer Res, 7(5):1181-1191. 

[134] Wang, B., He, M., Wang, L., 2013. Breast cancer screening among adult women in China, 2010. Prev Chronic Dis, 10:130136

[135] Wang, L., Li, D., Fu, Z., 2007. Association of CTLA-4 gene polymorphisms with sporadic breast cancer in Chinese Han population. BMC Cancer, 7(1):173

[136] Weiss, V.L., Lee, T.H., Song, H., 2012. Trafficking of high avidity HER-2/neu-specific T cells into HER-2/neu-expressing tumors after depletion of effector/memory-like regulatory T cells. PLoS ONE, 7(2):e31962

[137] Wendel, C., Hemping-Bovenkerk, A., Krasnyanska, J., 2012. CXCR4/CXCL12 participate in extravasation of metastasizing breast cancer cells within the liver in a rat model. PLoS ONE, 7(1):e30046

[138] Wiedermann, U., Davis, A.B., Zielinski, C.C., 2013. Vaccination for the prevention and treatment of breast cancer with special focus on Her-2/neu peptide vaccines. Breast Cancer Res Treat, 138(1):1-12. 

[139] Williams, S.A., Harata-Lee, Y., Comerford, I., 2010. Multiple functions of CXCL12 in a syngeneic model of breast cancer. Mol Cancer, 9(1):250

[140] Wolford, C.C., McConoughey, S.J., Jalgaonkar, S.P., 2013. Transcription factor ATF3 links host adaptive response to breast cancer metastasis. J Clin Invest, 123(7):2893-2906. 

[141] Wrzesinski, S.H., Wan, Y.Y., Flavell, R.A., 2007. Transforming growth factor-β and the immune response: implications for anticancer therapy. Clin Cancer Res, 13:5262-5270. 

[142] Wynn, T.A., Chawla, A., Pollard, J.W., 2013. Macrophage biology in development, homeostasis and disease. Nature, 496(7446):445-455. 

[143] Xie, G., Yao, Q., Liu, Y., 2012. IL-6-induced epithelial-mesenchymal transition promotes the generation of breast cancer stem-like cells analogous to mammosphere cultures. Int J Oncol, 40(4):1171-1179. 

[144] Yan, M., Jene, N., Byrne, D., 2011. Recruitment of regulatory T cells is correlated with hypoxia-induced CXCR4 expression, and is associated with poor prognosis in basal-like breast cancers. Breast Cancer Res, 13(2):R47

[145] Yang, J., Zhang, Z., Chen, C., 2013. MicroRNA-19a-3p inhibits breast cancer progression and metastasis by inducing macrophage polarization through downregulated expression of Fra-1 proto-oncogene. Oncogene, online,:

[146] Yang, J., Liao, D., Chen, C., 2013. Tumor-associated macrophages regulate murine breast cancer stem cells through a novel paracrine EGFR/Stat3/Sox-2 signaling pathway. Stem Cells, 31(2):248-258. 

[147] Yang, L., Qi, Y., Hu, J., 2012. Expression of Th17 cells in breast cancer tissue and its association with clinical parameters. Cell Biochem Biophys, 62(1):153-159. 

[148] Yu, J., Du, W., Yan, F., 2013. Myeloid-derived suppressor cells suppress antitumor immune responses through IDO expression and correlate with lymph node metastasis in patients with breast cancer. J Immunol, 190(7):3783-3797. 

[149] Yu, K.D., Di, G.H., Fan, L., 2010. Lack of an association between a functional polymorphism in the interleukin-6 gene promoter and breast cancer risk: a meta-analysis involving 25703 subjects. Breast Cancer Res Treat, 122(2):483-488. 

[150] Yu, M., Zhou, X., Niu, L., 2013. Targeting transmembrane TNF-α suppresses breast cancer growth. Cancer Res, 73(13):4061-4074. 

[151] Zhang, P., Su, D.M., Liang, M., 2008. Chemopreventive agents induce programmed death-1-ligand 1 (PD-L1) surface expression in breast cancer cells and promote PD-L1-mediated T cell apoptosis. Mol Immunol, 45(5):1470-1476. 

[152] Zhang, X., Tian, W., Cai, X., 2013. Hydrazinocurcumin encapsuled nanoparticles “re-educate” tumor-associated macrophages and exhibit anti-tumor effects on breast cancer following STAT3 suppression. PLoS ONE, 8(6):e65896

[153] Zhang, Y., Lv, D., Kim, H.J., 2013. A novel role of hematopoietic CCL5 in promoting triple-negative mammary tumor progression by regulating generation of myeloid-derived suppressor cells. Cell Res, 23(3):394-408. 

[154] Zhang, Y., Yang, P., Sun, T., 2013. miR-126 and miR-126* repress recruitment of mesenchymal stem cells and inflammatory monocytes to inhibit breast cancer metastasis. Nat Cell Biol, 15(3):284-294. 

[155] Zou, W., Chen, L., 2008. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol, 8(6):467-477. 

[156] Zou, W., Restifo, N.P., 2010. TH17 cells in tumour immunity and immunotherapy. Nat Rev Immunol, 10(4):248-256. 

Open peer comments: Debate/Discuss/Question/Opinion


zs@No address<No mail>

2014-02-08 11:02:53

The authors reviewed the interesting and hot topic the inflammation、immune system and Cancer and this review will help readers to know the recenlt advance concept and knowlege of this feild.

ZX@No address<No mail>

2014-02-08 11:01:43

The manuscript has a high significance for breast cancer study. The review mainly discuss a point that chronic inflammation in the tumor microenvironment promotes tumor growth and development. The effect of chronic inflammation on tumor has been a focus for recent years so the manuscript has a supernal novelty. This review may supply some important hints for immunotherapeutic strategies.

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