While detailed analysis of aberrant cancer cell signaling pathways and changes in cancer cell DNA has dominated the field of breast cancer biology for years, there now exists increasing evidence that the tumor microenvironment (TME) including tumor-infiltrating immune cells support the growth and development of breast cancer and further facilitate invasion and metastasis formation as well as sensitivity to drug therapy. Furthermore, breast cancer cells have developed different strategies to escape surveillance from the adaptive and innate immune system. These include loss of expression of immunostimulatory molecules, gain of expression of immunoinhibitory molecules such as PD-L1 and HLA-G, and altered expression of components involved in apoptosis. Furthermore, the composition of the TME plays a key role in breast cancer development and treatment response. In this review we will focus on i) the different immune evasion mechanisms used by breast cancer cells, ii) the role of immune cell infiltration in this disease, and (iii) implication for breast cancer-based immunotherapies.

Keywords:
Breast cancer, Immune escape, Immune surveillance, Tumor microenvironment, Immune response
1.
Rugo HS, Delord J-P, Im S-A, Tan A: Preliminary efficacy and safety of pembrolizumab (MK-3475) in patients with PD-L1-positive, estrogen receptor-positive (ER+)/HER2 negative advanced breast cancer enrolled in KEYNOTE-028. San Antonio Breast Cancer Symposium 2015;abstr S5-07.
2.
Solinas C, Gombos A, Latifyan S, et al: Targeting immune checkpoints in breast cancer: an update of early results. ESMO Open 2017;2:e000255.
3.
Mittal D, Gubin MM, Schreiber RD, Smyth MJ: New insights into cancer immunoediting and its three component phases - elimination, equilibrium and escape. Curr Opin Immunol 2014;27:16-25.
4.
Smyth MJ, Dunn GP, Schreiber RD: Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity. Adv Immunol 2006;90:1-50.
5.
Spranger S, Sivan A, Corrales L, Gajewski TF: Tumor and host factors controlling antitumor immunity and efficacy of cancer immunotherapy. Adv Immunol 2016;130:75-93.
6.
Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ: Natural innate and adaptive immunity to cancer. Annu Rev Immunol 2011;29:235-271.
7.
Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD: Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 2002;3:991-998.
8.
Schreiber RD, Old LJ, Smyth MJ: Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 2011;331:1565-1570.
9.
Hanahan D, Weinberg RA: Hallmarks of cancer: the next generation. Cell 2011;144:646-674.
10.
Fridman WH, Zitvogel L, Sautès-Fridman C, Kroemer G: The immune contexture in cancer prognosis and treatment. Nat Rev Clin Oncol 2017;14:717-734.
11.
Dushyanthen S, Beavis PA, Savas P, et al: Relevance of tumor-infiltrating lymphocytes in breast cancer. BMC Med 2015;13:202.
12.
Hendrickx W, Simeone I, Anjum S, et al: Identification of genetic determinants of breast cancer immune phenotypes by integrative genome-scale analysis. Oncoimmunology 2017;6:e1253654.
13.
Abd-Elsalam EA, Ismaeil NA: Melanoma-associated antigen genes: a new trend to predict the prognosis of breast cancer patients. Med Oncol 2014;31:285.
14.
Hou SY, Sang MX, Geng CZ, et al: Expressions of MAGE-A9 and MAGE-A11 in breast cancer and their expression mechanism. Arch Med Res 2014;45:44-51.
15.
Xu X, Tang X, Lu M, et al: Overexpression of MAGE-A9 predicts unfavorable outcome in breast cancer. Exp Mol Pathol 2014;97:579-584.
16.
Tchou J, Wang LC, Selven B, et al: Mesothelin, a novel immunotherapy target for triple negative breast cancer. Breast Cancer Res Treat 2012;133:799-804.
17.
Zieglschmid V, Hollmann C, Gutierrez B, et al: Heterogeneous expression of tumor-associated genes in disseminated breast cancer cells. Anticancer Res 2007;27:1769-1776.
18.
Mukherjee P, Tinder TL, Basu GD, et al: Therapeutic efficacy of MUC1-specific cytotoxic T lymphocytes and CD137 co-stimulation in a spontaneous breast cancer model. Breast Dis 2004;20:53-63.
19.
Nicolini A, Ferrari P, Duffy MJ: Prognostic and predictive biomarkers in breast cancer: past, present and future. Semin Cancer Biol 2017;pii:S1044-579X(17) 30052-4.
20.
Yan J, Liu XL, Han LZ, et al: Relation between Ki-67, ER, PR, Her2/neu, p21, EGFR, and TOP II-α expression in invasive ductal breast cancer patients and correlations with prognosis. Asian Pac J Cancer Prev 2015;16:823-829.
21.
Shokouh TZ, Ezatollah A, Barand P: Interrelationships between Ki67, HER2/neu, p53, ER, and PR status and their associations with tumor grade and lymph node involvement in breast carcinoma subtypes: retrospective-observational analytical study. Medicine (Baltimore) 2015;94:e1359.
22.
Hoff ER, Tubbs RR, Myles JL, Procop GW: HER2/neu amplification in breast cancer: stratification by tumor type and grade. Am J Clin Pathol 2002;117:916-921.
23.
Herrmann F, Lehr HA, Drexler I, et al: HER-2/neu-mediated regulation of components of the MHC class I antigen-processing pathway. Cancer Res 2004;64:215-220.
24.
Garrido F, Algarra I, García-Lora AM: The escape of cancer from T lymphocytes: immunoselection of MHC class I loss variants harboring structural-irreversible ‘hard' lesions. Cancer Immunol Immunother 2010;59:1601-1606.
25.
Seliger B, Jasinski-Bergner S, Quandt D, et al: HLA-E expression and its clinical relevance in human renal cell carcinoma. Oncotarget 2016;7:67360-67372.
26.
Respa A, Bukur J, Ferrone S, et al: Association of IFN-gamma signal transduction defects with impaired HLA class I antigen processing in melanoma cell lines. Clin Cancer Res 2011;17:2668-2678.
27.
Liu Y, Komohara Y, Domenick N, et al: Expression of antigen processing and presenting molecules in brain metastasis of breast cancer. Cancer Immunol Immunother 2012;61:789-801.
28.
Carbotti G, Nikpoor AR, Vacca P, et al: IL-27 mediates HLA class I up-regulation, which can be inhibited by the IL-6 pathway, in HLA-deficient small cell lung cancer cells. J Exp Clin Cancer Res 2017;36:140.
29.
Hanalioglu D, Ayvaz DC, Ozgur TT, et al: A novel mutation in TAP1 gene leading to MHC class I deficiency: report of two cases and review of the literature. Clin Immunol 2017;178:74-78.
30.
Wang M, Zhang C, Song Y, et al: Mechanism of immune evasion in breast cancer. Onco Targets Ther 2017;10:1561-1573.
31.
Zimmer J, Andrès E, Donato L, et al: Clinical and immunological aspects of HLA class I deficiency. QJM 2005;98:719-727.
32.
Ryschich E, Cebotari O, Fabian OV, et al: Loss of heterozygosity in the HLA class I region in human pancreatic cancer. Tissue Antigens 2004;64:696-702.
33.
Eichmüller SB, Osen W, Mandelboim O, Seliger B: Immune modulatory microRNAs involved in tumor attack and tumor immune escape. J Natl Cancer Inst 2017;109.
34.
Mariya T, Hirohashi Y, Torigoe T, et al: Prognostic impact of human leukocyte antigen class I expression and association of platinum resistance with immunologic profiles in epithelial ovarian cancer. Cancer Immunol Res 2014;2:1220-1229.
35.
Jobim MR, Jobim M, Salim PH, et al: Analysis of KIR gene frequencies and HLA class I genotypes in breast cancer and control group. Hum Immunol 2013;74:1130-1133.
36.
Kaneko K, Ishigami S, Kijima Y, et al: Clinical implication of HLA class I expression in breast cancer. BMC Cancer 2011;11:454.
37.
Garrido F, Cabrera T, Aptsiauri N: ‘Hard' and ‘soft' lesions underlying the HLA class I alterations in cancer cells: implications for immunotherapy. Int J Cancer 2010;127:249-256.
38.
Alegre E, Rizzo R, Bortolotti D, et al: Some basic aspects of HLA-G biology. J Immunol Res 2014;2014:657625.
39.
Morandi F, Rizzo R, Fainardi E, Rouas-Freiss N, Pistoia V: Recent advances in our understanding of HLA-G biology: lessons from a wide spectrum of human diseases. J Immunol Res 2016;2016:4326495.
40.
König L, Kasimir-Bauer S, Hoffmann O, et al: The prognostic impact of soluble and vesicular HLA-G and its relationship to circulating tumor cells in neoadjuvant treated breast cancer patients. Hum Immunol 2016;77:791-799.
41.
Engels CC, Fontein DB, Kuppen PJ, et al: Immunological subtypes in breast cancer are prognostic for invasive ductal but not for invasive lobular breast carcinoma. Br J Cancer 2014;111:532-538.
42.
De Kruijf EM, Engels CC, van de Water W, et al: Tumor immune subtypes distinguish tumor subclasses with clinical implications in breast cancer patients. Breast Cancer Res Treat 2013;142:355-364.
43.
Jeong S, Park S, Park BW, et al: Human leukocyte antigen-G (HLA-G) polymorphism and expression in breast cancer patients. PLoS One 2014;9:e98284.
44.
Urosevic M, Dummer R: Human leukocyte antigen-G and cancer immunoediting. Cancer Res 2008;68:627-630.
45.
Haghi M, Hosseinpour Feizi MA, Sadeghizadeh M, Lotfi AS: 14-bp Insertion/deletion polymorphism of the HLA-G gene in breast cancer among women from North Western Iran. Asian Pac J Cancer Prev 2015;16:6155-6158.
46.
Madjd Z, Spendlove I, Moss R, et al: Upregulation of MICA on high-grade invasive operable breast carcinoma. Cancer Immun 2007;7:17.
47.
Ishibashi K, Kumai T, Ohkuri T, et al: Epigenetic modification augments the immunogenicity of human leukocyte antigen G serving as a tumor antigen for T cell-based immunotherapy. Oncoimmunology 2016;5: e1169356.
48.
Dong H, Strome SE, Salomao DR, et al: Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 2002;8:793-800.
49.
Martin-Villalba A, Llorens-Bobadilla E, Wollny D: CD95 in cancer: tool or target? Trends Mol Med 2013;19:329-335.
50.
Bergmann-Leitner ES, Abrams SI: Positive and negative consequences of soluble Fas ligand produced by an antigen-specific CD4(+) T cell response in human carcinoma immune interactions. Cell Immunol 2001;209:49-62.
51.
Gutierrez LS, Eliza M, Niven-Fairchild T, Naftolin F, Mor G: The Fas/Fas-ligand system: a mechanism for immune evasion in human breast carcinomas. Breast Cancer Res Treat 1999;54:245-253.
52.
Le Gallo M, Poissonnier A, Blanco P, Legembre P: CD95/Fas, non-apoptotic signaling pathways, and kinases. Front Immunol 2017;8:1216.
53.
Fulda S, Meyer E, Debatin KM: Inhibition of TRAIL-induced apoptosis by Bcl-2 overexpression. Oncogene 2002;21:2283-2294.
54.
Zhivotovsky B, Orrenius S: Carcinogenesis and apoptosis: paradigms and paradoxes. Carcinogenesis 2006;27:1939-1945.
55.
Ryan BM, Konecny GE, Kahlert S, et al: Survivin expression in breast cancer predicts clinical outcome and is associated with HER2, VEGF, urokinase plasminogen activator and PAI-1. Ann Oncol 2006;17:597-604.
56.
Devarajan E, Sahin AA, Chen JS, et al: Down-regulation of caspase 3 in breast cancer: a possible mechanism for chemoresistance. Oncogene 2002;21:8843-8851.
57.
Grigoriev MY, Pozharissky KM, Hanson KP, Imyanitov EN, Zhivotovsky B: Expression of caspase-3 and -7 does not correlate with the extent of apoptosis in primary breast carcinomas. Cell Cycle 2002;1:337-342.
58.
Alsaab HO, Sau S, Alzhrani R, et al: PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcome. Front Pharmacol 2017;8:561.
59.
Taube JM, Galon J, Sholl LM, et al: Implications of the tumor immune microenvironment for staging and therapeutics. Mod Pathol 2017;DOI: 10.1038/modpathol.2017.156.
60.
Jadus MR, Natividad J, Mai A, et al: Lung cancer: a classic example of tumor escape and progression while providing opportunities for immunological intervention. Clin Dev Immunol 2012;2012:160724.
61.
Wang X, Sun Q, Liu Q, et al: CTC immune escape mediated by PD-L1. Med Hypotheses 2016;93:138-139.
62.
Li Z, Dong P, Ren M, et al: PD-L1 expression is associated with tumor FOXP3(+) regulatory T-cell infiltration of breast cancer and poor prognosis of patient. J Cancer 2016;7:784-793.
63.
Li CW, Lim SO, Xia W, et al: Glycosylation and stabilization of programmed death ligand-1 suppresses T-cell activity. Nat Commun 2016;7:12632.
64.
Bertucci F, Finetti P, Colpaert C, et al: PDL1 expression in inflammatory breast cancer is frequent and predicts for the pathological response to chemotherapy. Oncotarget 2015;6:13506-13519.
65.
Bertucci F, Finetti P, Birnbaum D, Mamessier E: The PD1/PDL1 axis, a promising therapeutic target in aggressive breast cancers. Oncoimmunology 2015;5: e1085148.
66.
McCullar B, Pandey M, Yaghmour G, et al: Genomic landscape of small cell carcinoma of the breast contrasted to small cell carcinoma of the lung. Breast Cancer Res Treat 2016;158:195-202.
67.
Beckers RK, Selinger CI, Vilain R, et al: Programmed death ligand 1 expression in triple-negative breast cancer is associated with tumour-infiltrating lymphocytes and improved outcome. Histopathology 2016;69:25-34.
68.
Soliman H, Khalil F, Antonia S: PD-L1 expression is increased in a subset of basal type breast cancer cells. PLoS One 2014;9:e88557.
69.
Guo L, Li W, Zhu X, et al: PD-L1 expression and CD274 gene alteration in triple-negative breast cancer: implication for prognostic biomarker. Springerplus 2016;5:805.
70.
Uhercik M, Sanders AJ, Owen S, et al: Clinical significance of PD1 and PDL1 in human breast cancer. Anticancer Res 2017;37:4249-4254.
71.
Sabatier R, Finetti P, Mamessier E, et al: Prognostic and predictive value of PDL1 expression in breast cancer. Oncotarget 2015;6:5449-5464.
72.
Nanda R, Chow LQ, Dees EC, et al: Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 study. J Clin Oncol 2016;34:2460-2467.
73.
Denkert C, von Minckwitz G, Brase JC, et al: Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers. J Clin Oncol 2015;33:983-991.
74.
Burugu S, Gao D, Leung S, Chia SK, Nielsen TO: LAG-3+ tumor infiltrating lymphocytes in breast cancer: clinical correlates and association with PD-1/PD-L1+ tumors. Ann Oncol 2017;28:2977-2984.
75.
Zhang H, Xiang R, Wu B, Li J, Luo G: T-cell immunoglobulin mucin-3 expression in invasive ductal breast carcinoma: clinicopathological correlations and association with tumor infiltration by cytotoxic lymphocytes. Mol Clin Oncol 2017;7:557-563.
76.
Liu C, Liu J, Wang J, et al: B7-H3 expression in ductal and lobular breast cancer and its association with IL-10. Mol Med Rep 2013;7:134-138.
77.
Petitprez F, Vano YA, Becht E, et al: Transcriptomic analysis of the tumor microenvironment to guide prognosis and immunotherapies. Cancer Immunol Immunother 2017;DOI: 10.1007/s00262-017-2058-z.
78.
Fridman WH, Pagès F, Sautès-Fridman C, Galon J: The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 2012;12:298-306.
79.
Domschke C, Schuetz F, Ge Y, et al: Intratumoral cytokines and tumor cell biology determine spontaneous breast cancer-specific immune responses and their correlation to prognosis. Cancer Res 2009;69:8420-8428.
80.
Rody A, Holtrich U, Pusztai L, et al: T-cell metagene predicts a favorable prognosis in estrogen receptor-negative and HER2-positive breast cancers. Breast Cancer Res 2009;11:R15.
81.
De Melo Gagliato D, Cortes J, Curigliano G, et al: Tumor-infiltrating lymphocytes in breast cancer and implications for clinical practice. Biochim Biophys Acta 2017;1868:527-537.
82.
Ibrahim M, Scozzi D, Toth K, et al: Naive CD4+ T cells carrying a TLR2 agonist overcome TGF-β-mediated tumor immune evasion. J Immunol 2018;200:847-856.
83.
Zhu S, Lin J, Qiao G, Wang X, Xu Y: Tim-3 identifies exhausted follicular helper T cells in breast cancer patients. Immunobiology 2016;221:986-993.
84.
Gu-Trantien C, Loi S, Garaud S, et al: CD4+ follicular helper T cell infiltration predicts breast cancer survival. J Clin Invest 2013;123:2873-2892.
85.
Schmidt M, Böhm D, von Törne C, et al: The humoral immune system has a key prognostic impact in node-negative breast cancer. Cancer Res 2008;68:5405-5413.
86.
Perou C, Jeffrey SS, van de Rijn M, et al: Distinctive gene expression patterns in human mammary epithelial cells and breast cancers. Proc Natl Acad Sci U S A 1999;96:9212-9217.
87.
Huang E, Cheng SH, Dressman H, et al: Gene expression predictors of breast cancer outcomes. Lancet 2003;361:1590-1596.
88.
Gil Del Alcazar CR, Huh SJ, Ekram MB, et al: Immune escape in breast cancer during in situ to invasive carcinoma transition. Cancer Discov 2017;7:1098-1115.
89.
Denkert C, Loibl S, Noske A, et al: Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol 2010;28:105-113.
90.
Loi S, Sirtaine N, Piette 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;31:860-867.
91.
Ali HR, Provenzano E, Dawson SJ, et al: Association between CD8+ T-cell infiltration and breast cancer survival in 12,439 patients. Ann Oncol 2014;25:1536-1543.
92.
Hugo W, Zaretsky JM, Sun L, et al: Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell 2016;165:35-44.
93.
Song C, Piva M, Sun L, et al: Recurrent tumor cell-intrinsic and -extrinsic alterations during MAPKi-induced melanoma regression and early adaptation. Cancer Discov 2017;7:1248-1265.
94.
Lu L, Xu X, Zhang B, Zhang R, Ji H, Wang X: Combined PD-1 blockade and GITR triggering induce a potent antitumor immunity in murine cancer models and synergizes with chemotherapeutic drugs. J Transl Med 2014;12:36.
© 2018 S. Karger GmbH, Freiburg
2018
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.