Skip to main content

Advertisement

Log in

Prognostic Value of Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer

  • Biomarkers (S Dawood, Section Editor)
  • Published:
Current Breast Cancer Reports Aims and scope Submit manuscript

Abstract

The adaptive immune system is a crucial component of cancer immunoediting and has emerged, in recent years, as a key foundation on which the success of novel cancer therapeutics have been built, namely the checkpoint inhibitors. Early observational studies have highlighted the importance of tumor-infiltrating lymphocytes (TILs) in patient outcomes across multiple solid tumor types, reflecting its role in cancer immunosurveillance. High TILs in triple-negative breast cancer (TNBC), a poor prognostic subgroup, has been shown to be associated with improved survival. When evaluated in functional TIL subsets, a positive correlation has also been observed with cytotoxic CD8+ TILs but results were conflicting for FOXP3 regulatory T cells. Overexpression of immune response genes corresponded to increased lymphocytic infiltration and improved outcomes in TNBC. Understanding the functional biology of TILs and its interaction with cancer in the immunoediting processes will help guide immunotherapeutic approaches in TNBC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Dent R, Hanna WM, Trudeau M, Rawlinson E, Sun P, Narod SA. Pattern of metastatic spread in triple-negative breast cancer. Breast Cancer Res Treat. 2009;115(2):423–8.

    Article  PubMed  Google Scholar 

  2. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature. 2000;406(6797):747–52.

    Article  CAS  PubMed  Google Scholar 

  3. Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med. 2010;363(20):1938–48.

    Article  CAS  PubMed  Google Scholar 

  4. Tischkowitz M, Brunet JS, Begin LR, Huntsman DG, Cheang MC, Akslen LA, et al. Use of immunohistochemical markers can refine prognosis in triple negative breast cancer. BMC Cancer. 2007;7:134.

    Article  PubMed Central  PubMed  Google Scholar 

  5. Prat A, Perou CM. Deconstructing the molecular portraits of breast cancer. Mol Oncol. 2011;5(1):5–23.

    Article  CAS  PubMed  Google Scholar 

  6. Prat A, Adamo B, Cheang MC, Anders CK, Carey LA, Perou CM. Molecular characterization of basal-like and non-basal-like triple-negative breast cancer. Oncologist. 2013;18(2):123–33.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011;121(7):2750–67.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Cheang MC, Voduc D, Bajdik C, Leung S, McKinney S, Chia SK, et al. Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype. Clin Cancer Res. 2008;14(5):1368–76.

    Article  CAS  PubMed  Google Scholar 

  9. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014;384(9948):1109–17.

    Article  CAS  PubMed  Google Scholar 

  11. Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373:123–35.

    Article  CAS  PubMed  Google Scholar 

  12. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 2002;3(11):991–8.

    Article  CAS  PubMed  Google Scholar 

  13. Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol. 2004;22:329–60.

    Article  CAS  PubMed  Google Scholar 

  14. Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, et al. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature. 2001;410(6832):1107–11.

    Article  CAS  PubMed  Google Scholar 

  15. Aaltomaa S, Lipponen P, Eskelinen M, Kosma VM, Marin S, Alhava E, et al. Lymphocyte infiltrates as a prognostic variable in female breast cancer. Eur J Cancer. 1992;28A(4-5):859–64.

    Article  CAS  PubMed  Google Scholar 

  16. Clark Jr WH, Elder DE, Guerry D, Braitman LE, Trock BJ, Schultz D, et al. Model predicting survival in stage I melanoma based on tumor progression. J Natl Cancer Inst. 1989;81(24):1893–904.

    Article  PubMed  Google Scholar 

  17. Jass JR. Lymphocytic infiltration and survival in rectal cancer. J Clin Pathol. 1986;39(6):585–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Lipponen PK, Eskelinen MJ, Jauhiainen K, Harju E, Terho R. Tumour infiltrating lymphocytes as an independent prognostic factor in transitional cell bladder cancer. Eur J Cancer. 1992;29A(1):69–75.

    CAS  PubMed  Google Scholar 

  19. Nacopoulou L, Azaris P, Papacharalampous N, Davaris P. Prognostic significance of histologic host response in cancer of the large bowel. Cancer. 1981;47(5):930–6.

    Article  CAS  PubMed  Google Scholar 

  20. Rilke F, Colnaghi MI, Cascinelli N, Andreola S, Baldini MT, Bufalino R, et al. Prognostic significance of HER-2/neu expression in breast cancer and its relationship to other prognostic factors. Int J Cancer. 1991;49(1):44–9.

    Article  CAS  PubMed  Google Scholar 

  21. 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.

    PubMed  Google Scholar 

  22. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Torhorst J, Bucher C, Kononen J, Haas P, Zuber M, Kochli OR, et al. Tissue microarrays for rapid linking of molecular changes to clinical endpoints. Am J Pathol. 2001;159(6):2249–56.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Liu S, Foulkes WD, Leung S, Gao D, Lau S, Kos Z, et al. Prognostic significance of FOXP3+ tumor-infiltrating lymphocytes in breast cancer depends on estrogen receptor and human epidermal growth factor receptor-2 expression status and concurrent cytotoxic T-cell infiltration. Breast Cancer Res. 2014;16(5):432.

    Article  PubMed Central  PubMed  Google Scholar 

  25. Loi S, Michiels S, Salgado R, Sirtaine N, Jose V, Fumagalli D, et al. Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Ann Oncol. 2014;25(8):1544–50.

    Article  CAS  PubMed  Google Scholar 

  26. 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.

    Article  CAS  PubMed  Google Scholar 

  27. Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs working group 2014. Ann Oncol. 2015;26(2):259–71.

    Article  CAS  PubMed  Google Scholar 

  28. 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.

    Article  CAS  PubMed  Google Scholar 

  29. Bertucci F, Finetti P, Cervera N, Esterni B, Hermitte F, Viens P, et al. How basal are triple-negative breast cancers? Int J Cancer. 2008;123(1):236–40.

    Article  CAS  PubMed  Google Scholar 

  30. Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, Hernandez-Boussard T, Livasy C, Cowan D, Dressler L, et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res. 2004;10(16):5367–74.

  31. 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. 2010;29(15):1949–55.

    Article  Google Scholar 

  32. Ali HR, Provenzano E, Dawson SJ, Blows FM, Liu B, Shah M, et al. Association between CD8+ T-cell infiltration and breast cancer survival in 12,439 patients. Ann Oncol. 2014;25(8):1536–43.

    Article  CAS  PubMed  Google Scholar 

  33. 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.

    Article  CAS  PubMed  Google Scholar 

  34. Yan M, Jene N, Byrne D, Millar EK, O’Toole SA, McNeil CM, et al. 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. 2011;13(2):R47.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. 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.

    Article  CAS  PubMed  Google Scholar 

  36. Dieci MV, Mathieu MC, Guarneri V, Conte P, Delaloge S, Andre F, and Goubar A. Prognostic and predictive value of tumor-infiltrating lymphocytes in two phase III randomized adjuvant breast cancer trials. Ann Oncol. 2015

  37. Adams S, Gray RJ, Demaria S, Goldstein L, Perez EA, Shulman LN, et al. Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J Clin Oncol. 2014;32(27):2959–66.

    Article  PubMed Central  PubMed  Google Scholar 

  38. Loi S. Host antitumor immunity plays a role in the survival of patients with newly diagnosed triple-negative breast cancer. J Clin Oncol. 2014;32(27):2935–7.

    Article  PubMed  Google Scholar 

  39. Dobrzanski MJ, Reome JB, Hylind JC, Rewers-Felkins KA. CD8-mediated type 1 antitumor responses selectively modulate endogenous differentiated and nondifferentiated T cell localization, activation, and function in progressive breast cancer. J Immunol. 2006;177(11):8191–201.

    Article  CAS  PubMed  Google Scholar 

  40. 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.

    Article  CAS  PubMed  Google Scholar 

  41. Chen Z, Chen X, Zhou E, Chen G, Qian K, Wu X, et al. Intratumoral CD8(+) cytotoxic lymphocyte is a favorable prognostic marker in node-negative breast cancer. PLoS One. 2014;9(4), e95475.

    Article  PubMed Central  PubMed  Google Scholar 

  42. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133(5):775–87.

    Article  CAS  PubMed  Google Scholar 

  43. Gobert M, Treilleux I, Bendriss-Vermare N, Bachelot T, Goddard-Leon S, Arfi V, et al. 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. 2009;69(5):2000–9.

    Article  CAS  PubMed  Google Scholar 

  44. Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity. 2005;22(3):329–41.

    Article  CAS  PubMed  Google Scholar 

  45. Qin FX. Dynamic behavior and function of Foxp3+ regulatory T cells in tumor bearing host. Cell Mol Immunol. 2009;6(1):3–13.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Bates GJ, Fox SB, Han C, Leek RD, Garcia JF, Harris AL, et al. Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol. 2006;24(34):5373–80.

    Article  PubMed  Google Scholar 

  47. 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.

    Article  CAS  PubMed  Google Scholar 

  48. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Takenaka M, Seki N, Toh U, Hattori S, Kawahara A, Yamaguchi T, et al. FOXP3 expression in tumor cells and tumor-infiltrating lymphocytes is associated with breast cancer prognosis. Mol Clin Oncol. 2013;1(4):625–32.

    PubMed Central  PubMed  Google Scholar 

  50. Wei S, Kryczek I, Zou W. Regulatory T-cell compartmentalization and trafficking. Blood. 2006;108(2):426–31.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Nelson BH. CD20+ B cells: the other tumor-infiltrating lymphocytes. J Immunol. 2010;185(9):4977–82.

    Article  CAS  PubMed  Google Scholar 

  52. Marsigliante S, Biscozzo L, Marra A, Nicolardi G, Leo G, Lobreglio GB, et al. Computerised counting of tumour infiltrating lymphocytes in 90 breast cancer specimens. Cancer Lett. 1999;139(1):33–41.

    Article  CAS  PubMed  Google Scholar 

  53. Helal TE, Ibrahim EA, Alloub AI. Immunohistochemical analysis of tumor-infiltrating lymphocytes in breast carcinoma: relation to prognostic variables. Indian J Pathol Microbiol. 2013;56(2):89–93.

    Article  PubMed  Google Scholar 

  54. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704.

    Article  CAS  PubMed  Google Scholar 

  55. Muenst S, Soysal SD, Gao F, Obermann EC, Oertli D, Gillanders WE. 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. 2013;139(3):667–76.

    Article  CAS  PubMed  Google Scholar 

  56. Ghebeh H, Barhoush E, Tulbah A, Elkum N, Al-Tweigeri T, Dermime S. FOXP3+ Tregs and B7-H1+/PD-1+ T lymphocytes co-infiltrate the tumor tissues of high-risk breast cancer patients: implication for immunotherapy. BMC Cancer. 2008;8:57.

    Article  PubMed Central  PubMed  Google Scholar 

  57. Sun S, Fei X, Mao Y, Wang X, Garfield DH, Huang O, et al. PD-1(+) immune cell infiltration inversely correlates with survival of operable breast cancer patients. Cancer Immunol Immunother. 2014;63(4):395–406.

    Article  CAS  PubMed  Google Scholar 

  58. Sotiriou C, Piccart MJ. Taking gene-expression profiling to the clinic: when will molecular signatures become relevant to patient care? Nat Rev Cancer. 2007;7(7):545–53.

    Article  CAS  PubMed  Google Scholar 

  59. Sotiriou C, Pusztai L. Gene-expression signatures in breast cancer. N Engl J Med. 2009;360(8):790–800.

    Article  CAS  PubMed  Google Scholar 

  60. Jezequel P, Loussouarn D, Guerin-Charbonnel C, Campion L, Vanier A, Gouraud W, et al. Gene-expression molecular subtyping of triple-negative breast cancer tumours: importance of immune response. Breast Cancer Res. 2015;17:43.

    Article  PubMed Central  PubMed  Google Scholar 

  61. 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.

    Article  PubMed Central  PubMed  Google Scholar 

  62. Kreike B, van Kouwenhove M, Horlings H, Weigelt B, Peterse H, Bartelink H, et al. Gene expression profiling and histopathological characterization of triple-negative/basal-like breast carcinomas. Breast Cancer Res. 2007;9(5):R65.

    Article  PubMed Central  PubMed  Google Scholar 

  63. 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.

    Article  CAS  PubMed  Google Scholar 

  64. Rody A, Holtrich U, Pusztai L, Liedtke C, Gaetje R, Ruckhaeberle E, et al. T-cell metagene predicts a favorable prognosis in estrogen receptor-negative and HER2-positive breast cancers. Breast Cancer Res. 2009;11(2):R15.

    Article  PubMed Central  PubMed  Google Scholar 

  65. Lee HJ, Lee JJ, Song IH, Park IA, Kang J, Yu JH, et al. Prognostic and predictive value of NanoString-based immune-related gene signatures in a neoadjuvant setting of triple-negative breast cancer: relationship to tumor-infiltrating lymphocytes. Breast Cancer Res Treat. 2015;151(3):619–27.

    Article  CAS  PubMed  Google Scholar 

  66. Sabatier R, Finetti P, Cervera N, Lambaudie E, Esterni B, Mamessier E, et al. A gene expression signature identifies two prognostic subgroups of basal breast cancer. Breast Cancer Res Treat. 2011;126(2):407–20.

    Article  CAS  PubMed  Google Scholar 

  67. Nagalla S, Chou JW, Willingham MC, Ruiz J, Vaughn JP, Dubey P, et al. Interactions between immunity, proliferation and molecular subtype in breast cancer prognosis. Genome Biol. 2013;14(4):R34.

    Article  PubMed Central  PubMed  Google Scholar 

  68. DuPage M, Mazumdar C, Schmidt LM, Cheung AF, Jacks T. Expression of tumour-specific antigens underlies cancer immunoediting. Nature. 2012;482(7385):405–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  69. Boon T, Cerottini JC, Van den Eynde B, van der Bruggen P, Van Pel A. Tumor antigens recognized by T lymphocytes. Annu Rev Immunol. 1994;12:337–65.

    Article  CAS  PubMed  Google Scholar 

  70. Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499(7457):214–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  71. Schumacher TN, and Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015;348(6230):69–74.

  72. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61-70.

  73. Weigelt B, Baehner FL, Reis-Filho JS. The contribution of gene expression profiling to breast cancer classification, prognostication and prediction: a retrospective of the last decade. J Pathol. 2010;220(2):263–80.

  74. Zuo T, Wang L, Morrison C, Chang X, Zhang H, Li W, et al. FOXP3 is an X-linked breast cancer suppressor gene and an important repressor of the HER-2/ErbB2 oncogene. Cell. 2007;129(7):1275–86.

  75. Merlo A, Casalini P, Carcangiu ML, Malventano C, Triulzi T, Menard S, et al. FOXP3 expression and overall survival in breast cancer. J Clin Oncol. 2009;27(11):1746–52.

  76. 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.

  77. Spranger S, Spaapen RM, Zha Y, Williams J, Meng Y, Ha TT, et al. Up-regulation of PD-L1, IDO, and T (regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci Transl Med. 2013;5(200):200ra116.

  78. Olkhanud PB, Damdinsuren B, Bodogai M, Gress RE, Sen R, Wejksza K, et al. Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4(+) T cells to T-regulatory cells. Cancer Res. 2011;71(10):3505–15.

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Koo Si-Lin, Loh Kiley, Sulastri Kamis, Jabed Iqbal, Rebecca Dent, and Yap Yoon Sim declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Koo Si-Lin.

Additional information

This article is part of the Topical Collection on Biomarkers

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Si-Lin, K., Kiley, L., Kamis, S. et al. Prognostic Value of Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer. Curr Breast Cancer Rep 7, 232–241 (2015). https://doi.org/10.1007/s12609-015-0196-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12609-015-0196-x

Keywords

Navigation