Abstract
It has become increasingly evident that immune cells can control the clinical progression of breast cancer. In addition, certain chemotherapeutic drugs and targeted therapies used for treatment of breast cancer have been shown to modulate immunity as part of their mechanism of action. Thus, analysis of tumor-infiltrating immune cells and their pro- and antitumor effects offers the hope of prognostic information and the identification of patients most likely to respond to immunotherapies. In this chapter, we discuss the role of the immune system in breast cancer, with a focus on the prognostic value of specific immune cell subsets and how these could be harnessed or inhibited for the treatment of certain types of breast cancer. Particularly, we discuss the large amount of preclinical and correlative data that associates immune infiltrates, cells, and immune gene signatures with prognosis and therapeutic efficacy in estrogen receptor-negative and HER2+ breast cancer.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Penn I. Tumors of the immunocompromised patient. Annu Rev Med. 1988;39:63–73.
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.
Stagg J, Johnstone RW, Smyth MJ. From cancer immunosurveillance to cancer immunotherapy. Immunol Rev. 2007;220:82–101.
Mlecnik B, Bindea G, Pages F, Galon J. Tumor immunosurveillance in human cancers. Cancer Metastasis Rev. 2011;30(1):5–12.
Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12(4):298–306.
Denkert C, Loibl S, Noske A, Roller M, Muller BM, Komor M, et al. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol. 2010;28(1):105–13.
Mahmoud SM, Paish EC, Powe DG, Macmillan RD, Grainge MJ, Lee AH, et al. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin Oncol. 2011;29(15):1949–55.
Loi S, Sirtaine N, Piette F, Salgado R, Viale G, Van Eenoo F, et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol. 2013;31(7):860–7.
Finak G, Bertos N, Pepin F, Sadekova S, Souleimanova M, Zhao H, et al. Stromal gene expression predicts clinical outcome in breast cancer. Nat Med. 2008;14(5):518–27.
Baker K, Lachapelle J, Zlobec I, Bismar TA, Terracciano L, Foulkes WD. Prognostic significance of CD8+ T lymphocytes in breast cancer depends upon both oestrogen receptor status and histological grade. Histopathology. 2011;58(7):1107–16.
Teschendorff AE, Miremadi A, Pinder SE, Ellis IO, Caldas C. An immune response gene expression module identifies a good prognosis subtype in estrogen receptor negative breast cancer. Genome Biol. 2007;8(8):R157.
DeNardo DG, Brennan DJ, Rexhepaj E, Ruffell B, Shiao SL, Madden SF, et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov. 2011;1(1):54–67.
Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995;155(3):1151–64.
Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet. 2001;27(1):20–1.
Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB, Yasayko SA, et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet. 2001;27(1):68–73.
Wildin RS, Ramsdell F, Peake J, Faravelli F, Casanova JL, Buist N, et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet. 2001;27(1):18–20.
Mahmoud SM, Paish EC, Powe DG, Macmillan RD, Lee AH, Ellis IO, et al. An evaluation of the clinical significance of FOXP3+ infiltrating cells in human breast cancer. Breast Cancer Res Treat. 2011;127(1):99–108.
Liu F, Lang R, Zhao J, Zhang X, Pringle GA, Fan Y, et al. CD8(+) cytotoxic T cell and FOXP3(+) regulatory T cell infiltration in relation to breast cancer survival and molecular subtypes. Breast Cancer Res Treat. 2011;130(2):645–55.
Liu F, Li Y, Ren M, Zhang X, Guo X, Lang R, et al. Peritumoral FOXP3(+) regulatory T cell is sensitive to chemotherapy while intratumoral FOXP3(+) regulatory T cell is prognostic predictor of breast cancer patients. Breast Cancer Res Treat. 2012;135(2):459–67.
Ladoire S, Mignot G, Dabakuyo S, Arnould L, Apetoh L, Rebe C, et al. In situ immune response after neoadjuvant chemotherapy for breast cancer predicts survival. J Pathol. 2011;224(3):389–400.
Oda N, Shimazu K, Naoi Y, Morimoto K, Shimomura A, Shimoda M, et al. Intratumoral regulatory T cells as an independent predictive factor for pathological complete response to neoadjuvant paclitaxel followed by 5-FU/epirubicin/cyclophosphamide in breast cancer patients. Breast Cancer Res Treat. 2012;136(1):107–16.
Lee S, Cho EY, Park YH, Ahn JS, Im YH. Prognostic impact of FOXP3 expression in triple-negative breast cancer. Acta Oncol. 2013;52(1):73–81.
West NR, Kost SE, Martin SD, Milne K, Deleeuw RJ, Nelson BH, et al. Tumour-infiltrating FOXP3(+) lymphocytes are associated with cytotoxic immune responses and good clinical outcome in oestrogen receptor-negative breast cancer. Br J Cancer. 2013;108(1):155–62.
Gu-Trantien C, Loi S, Garaud S, Equeter C, Libin M, de Wind A, et al. CD4+ follicular helper T cell infiltration predicts breast cancer survival. J Clin Invest. 2013;123(7):2873–92.
Schmidt M, Bohm D, von Torne C, Steiner E, Puhl A, Pilch H, et al. The humoral immune system has a key prognostic impact in node-negative breast cancer. Cancer Res. 2008;68(13):5405–13.
Schmidt M, Hellwig B, Hammad S, Othman A, Lohr M, Chen Z, et al. A comprehensive analysis of human gene expression profiles identifies stromal immunoglobulin kappa C as a compatible prognostic marker in human solid tumors. Clin Cancer Res. 2012;18(9):2695–703.
Mahmoud SM, Lee AH, Paish EC, Macmillan RD, Ellis IO, Green AR. The prognostic significance of B lymphocytes in invasive carcinoma of the breast. Breast Cancer Res Treat. 2012;132(2):545–53.
DeNardo DG, Barreto JB, Andreu P, Vasquez L, Tawfik D, Kolhatkar N, et al. CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell. 2009;16(2):91–102.
Bunt SK, Yang L, Sinha P, Clements VK, Leips J, Ostrand-Rosenberg S. Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression. Cancer Res. 2007;67(20):10019–26.
Serafini P, Borrello I, Bronte V. Myeloid suppressor cells in cancer: recruitment, phenotype, properties, and mechanisms of immune suppression. Semin Cancer Biol. 2006;16(1):53–65.
Sceneay J, Chow MT, Chen A, Halse HM, Wong CS, Andrews DM, et al. Primary tumor hypoxia recruits CD11b+/Ly6Cmed/Ly6G+ immune suppressor cells and compromises NK cell cytotoxicity in the premetastatic niche. Cancer Res. 2012;72(16):3906–11.
Filipazzi P, Valenti R, Huber V, Pilla L, Canese P, Iero M, et al. Identification of a new subset of myeloid suppressor cells in peripheral blood of melanoma patients with modulation by a granulocyte-macrophage colony-stimulation factor-based antitumor vaccine. J Clin Oncol. 2007;25(18):2546–53.
Desmedt C, Haibe-Kains B, Wirapati P, Buyse M, Larsimont D, Bontempi G, et al. Biological processes associated with breast cancer clinical outcome depend on the molecular subtypes. Clin Cancer Res. 2008;14(16):5158–65.
Ignatiadis M, Singhal SK, Desmedt C, Haibe-Kains B, Criscitiello C, Andre F, et al. Gene modules and response to neoadjuvant chemotherapy in breast cancer subtypes: a pooled analysis. J Clin Oncol. 2012;30(16):1996–2004.
Liu S, Lachapelle J, Leung S, Gao D, Foulkes WD, Nielsen TO. CD8+ lymphocyte infiltration is an independent favorable prognostic indicator in basal-like breast cancer. Breast Cancer Res. 2012;14(2):R48.
Rody A, Karn T, Liedtke C, Pusztai L, Ruckhaeberle E, Hanker L, et al. A clinically relevant gene signature in triple negative and basal-like breast cancer. Breast Cancer Res. 2011;13(5):R97.
Ha NH, Nair VS, Reddy DN, Mudvari P, Ohshiro K, Ghanta KS, et al. Lactoferrin-endothelin-1 axis contributes to the development and invasiveness of triple-negative breast cancer phenotypes. Cancer Res. 2011;71(23):7259–69.
Grigoriadis A, Caballero OL, Hoek KS, da Silva L, Chen YT, Shin SJ, et al. CT-X antigen expression in human breast cancer. Proc Natl Acad Sci U S A. 2009;106(32):13493–8.
Curigliano G, Viale G, Ghioni M, Jungbluth AA, Bagnardi V, Spagnoli GC, et al. Cancer-testis antigen expression in triple-negative breast cancer. Ann Oncol Off J Eur Soc Med Oncol ESMO. 2011;22(1):98–103.
Chen YT, Ross DS, Chiu R, Zhou XK, Chen YY, Lee P, et al. Multiple cancer/testis antigens are preferentially expressed in hormone-receptor negative and high-grade breast cancers. PLoS One. 2011;6(3):e17876.
Karn T, Pusztai L, Ruckhaberle E, Liedtke C, Muller V, Schmidt M, et al. Melanoma antigen family A identified by the bimodality index defines a subset of triple negative breast cancers as candidates for immune response augmentation. Eur J Cancer. 2012;48(1):12–23.
Spychala J, Lazarowski E, Ostapkowicz A, Ayscue LH, Jin A, Mitchell BS. Role of estrogen receptor in the regulation of ecto-5′-nucleotidase and adenosine in breast cancer. Clin Cancer Res. 2004;10(2):708–17.
Stagg J, Divisekera U, McLaughlin N, Sharkey J, Pommey S, Denoyer D, et al. Anti-CD73 antibody therapy inhibits breast tumor growth and metastasis. Proc Natl Acad Sci U S A. 2010;107(4):1547–52.
Stagg J, Divisekera U, Duret H, Sparwasser T, Teng MW, Darcy PK, et al. CD73-deficient mice have increased antitumor immunity and are resistant to experimental metastasis. Cancer Res. 2011;71(8):2892–900.
Stagg J, Beavis PA, Divisekera U, Liu MC, Moller A, Darcy PK, et al. CD73-deficient mice are resistant to carcinogenesis. Cancer Res. 2012;72(9):2190–6.
Wang L, Fan J, Thompson LF, Zhang Y, Shin T, Curiel TJ, et al. CD73 has distinct roles in nonhematopoietic and hematopoietic cells to promote tumor growth in mice. J Clin Invest. 2011;121(6):2371–82.
Yegutkin GG, Marttila-Ichihara F, Karikoski M, Niemela J, Laurila JP, Elima K, et al. Altered purinergic signaling in CD73-deficient mice inhibits tumor progression. Eur J Immunol. 2011;41(5):1231–41.
Ferris RL, Jaffee EM, Ferrone S. Tumor antigen-targeted, monoclonal antibody-based immunotherapy: clinical response, cellular immunity, and immunoescape. J Clin Oncol. 2010;28(28):4390–9.
Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med. 2000;6(4):443–6.
Park S, Jiang Z, Mortenson ED, Deng L, Radkevich-Brown O, Yang X, et al. The therapeutic effect of anti-HER2/neu antibody depends on both innate and adaptive immunity. Cancer Cell. 2010;18(2):160–70.
Stagg J, Loi S, Divisekera U, Ngiow SF, Duret H, Yagita H, et al. Anti-ErbB-2 mAb therapy requires type I and II interferons and synergizes with anti-PD-1 or anti-CD137 mAb therapy. Proc Natl Acad Sci U S A. 2011;108(17):7142–7.
Pencina MJ, d’Agostino RB. Overall C as a measure of discrimination in survival analysis: model specific population value and confidence interval estimation. Stat Med. 2004;23:2109–23.
Ju T, Cummings RD. A unique molecular chaperone Cosmc required for activity of the mammalian core 1 beta 3-galactosyltransferase. Proc Natl Acad Sci U S A. 2002;99(26):16613–8.
von Mensdorff-Pouilly S, Verstraeten AA, Kenemans P, Snijdewint FG, Kok A, Van Kamp GJ, et al. Survival in early breast cancer patients is favorably influenced by a natural humoral immune response to polymorphic epithelial mucin. J Clin Oncol. 2000;18(3):574–83.
Brossart P, Heinrich KS, Stuhler G, Behnke L, Reichardt VL, Stevanovic S, et al. Identification of HLA-A2-restricted T-cell epitopes derived from the MUC1 tumor antigen for broadly applicable vaccine therapies. Blood. 1999;93(12):4309–17.
Lakshminarayanan V, Thompson P, Wolfert MA, Buskas T, Bradley JM, Pathangey LB, et al. Immune recognition of tumor-associated mucin MUC1 is achieved by a fully synthetic aberrantly glycosylated MUC1 tripartite vaccine. Proc Natl Acad Sci U S A. 2012;109(1):261–6.
Arteaga CL, Sliwkowski MX, Osborne CK, Perez EA, Puglisi F, Gianni L. Treatment of HER2-positive breast cancer: current status and future perspectives. Nat Rev Clin Oncol. 2012;9(1):16–32.
Disis ML, Wallace DR, Gooley TA, Dang Y, Slota M, Lu H, et al. Concurrent trastuzumab and HER2/neu-specific vaccination in patients with metastatic breast cancer. J Clin Oncol. 2009;27(28):4685–92.
Tyagi P, Mirakhur B. MAGRIT: the largest-ever phase III lung cancer trial aims to establish a novel tumor-specific approach to therapy. Clin Lung Cancer. 2009;10(5):371–4.
Quezada SA, Peggs KS, Curran MA, Allison JP. CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. J Clin Invest. 2006;116(7):1935–45.
Chen H, Liakou CI, Kamat A, Pettaway C, Ward JF, Tang DN, et al. Anti-CTLA-4 therapy results in higher CD4+ICOShi T cell frequency and IFN-gamma levels in both nonmalignant and malignant prostate tissues. Proc Natl Acad Sci U S A. 2009;106(8):2729–34.
Kahler KC, Hauschild A. Treatment and side effect management of CTLA-4 antibody therapy in metastatic melanoma. J Dtsch Dermatol Ges. 2011;9(4):277–86.
Hirano F, Kaneko K, Tamura H, Dong H, Wang S, Ichikawa M, et al. Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res. 2005;65(3):1089–96.
Gao Q, Wang XY, Qiu SJ, Yamato I, Sho M, Nakajima Y, et al. Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res. 2009;15(3):971–9.
Gadiot J, Hooijkaas AI, Kaiser AD, van Tinteren H, van Boven H, Blank C. Overall survival and PD-L1 expression in metastasized malignant melanoma. Cancer. 2011;117(10):2192–201.
Zhang P, Su DM, Liang M, Fu J. 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. 2008;45(5):1470–6.
Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–65.
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54.
Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Safety and tumor responses with lambrolizumab (Anti-PD-1) in melanoma. N Engl J Med. 2013;369(2):134–44.
Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A. 2010;107(9):4275–80.
Ghebeh H, Lehe C, Barhoush E, Al-Romaih K, Tulbah A, Al-Alwan M, et al. Doxorubicin downregulates cell surface B7-H1 expression and upregulates its nuclear expression in breast cancer cells: role of B7-H1 as an anti-apoptotic molecule. Breast Cancer Res. 2010;12(4):R48.
Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, Anderson AC. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med. 2010;207(10):2187–94.
Ngiow SF, von Scheidt B, Akiba H, Yagita H, Teng MW, Smyth MJ. Anti-TIM3 antibody promotes T cell IFN-gamma-mediated antitumor immunity and suppresses established tumors. Cancer Res. 2011;71(10):3540–51.
Rangachari M, Zhu C, Sakuishi K, Xiao S, Karman J, Chen A, et al. Bat3 promotes T cell responses and autoimmunity by repressing Tim-3-mediated cell death and exhaustion. Nat Med. 2012;18(9):1394–400.
Chiba S, Baghdadi M, Akiba H, Yoshiyama H, Kinoshita I, Dosaka-Akita H, et al. Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. Nat Immunol. 2012;13(9):832–42.
Woo SR, Turnis ME, Goldberg MV, Bankoti J, Selby M, Nirschl CJ, et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 2012;72(4):917–27.
Croft M, Duan W, Choi H, Eun SY, Madireddi S, Mehta A. TNF superfamily in inflammatory disease: translating basic insights. Trends Immunol. 2012;33(3):144–52.
Piconese S, Valzasina B, Colombo MP. OX40 triggering blocks suppression by regulatory T cells and facilitates tumor rejection. J Exp Med. 2008;205(4):825–39.
Narazaki H, Zhu Y, Luo L, Zhu G, Chen L. CD137 agonist antibody prevents cancer recurrence: contribution of CD137 on both hematopoietic and nonhematopoietic cells. Blood. 2010;115(10):1941–8.
Palazon A, Teijeira A, Martinez-Forero I, Hervas-Stubbs S, Roncal C, Penuelas I, et al. Agonist anti-CD137 mAb act on tumor endothelial cells to enhance recruitment of activated T lymphocytes. Cancer Res. 2011;71(3):801–11.
Langowski JL, Zhang X, Wu L, Mattson JD, Chen T, Smith K, et al. IL-23 promotes tumour incidence and growth. Nature. 2006;442(7101):461–5.
Teng MW, von Scheidt B, Duret H, Towne JE, Smyth MJ. Anti-IL-23 monoclonal antibody synergizes in combination with targeted therapies or IL-2 to suppress tumor growth and metastases. Cancer Res. 2011;71(6):2077–86.
Gangemi S, Minciullo P, Adamo B, Franchina T, Ricciardi GR, Ferraro M, et al. Clinical significance of circulating interleukin-23 as a prognostic factor in breast cancer patients. J Cell Biochem. 2012;113(6):2122–5.
Singer K, Gottfried E, Kreutz M, Mackensen A. Suppression of T-cell responses by tumor metabolites. Cancer Immunol Immunother. 2011;60(3):425–31.
Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, Phan GQ, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res. 2011;17(13):4550–7.
Jena B, Dotti G, Cooper LJ. Redirecting T-cell specificity by introducing a tumor-specific chimeric antigen receptor. Blood. 2010;116(7):1035–44.
Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365(8):725–33.
Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther. 2010;18(4):843–51.
Tchou J, Wang LC, Selven B, Zhang H, Conejo-Garcia J, Borghaei H, et al. Mesothelin, a novel immunotherapy target for triple negative breast cancer. Breast Cancer Res Treat. 2012;133(2):799–804.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2015 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Stagg, J., Loi, S. (2015). Immunology and Immunotherapy of Breast Cancer. In: Rezaei, N. (eds) Cancer Immunology. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-46410-6_23
Download citation
DOI: https://doi.org/10.1007/978-3-662-46410-6_23
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-46409-0
Online ISBN: 978-3-662-46410-6
eBook Packages: MedicineMedicine (R0)