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BMC Medicine
Published in: BMC Medicine 1/2015

Open Access 01-12-2015 | Minireview

Relevance of tumor-infiltrating lymphocytes in breast cancer

Authors: Sathana Dushyanthen, Paul A. Beavis, Peter Savas, Zhi Ling Teo, Chenhao Zhou, Mariam Mansour, Phillip K. Darcy, Sherene Loi

Published in: BMC Medicine | Issue 1/2015

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Abstract

While breast cancer has not been considered a cancer amenable to immunotherapeutic approaches, recent studies have demonstrated evidence of significant immune cell infiltration via tumor-infiltrating lymphocytes in a subset of patient tumors. In this review we present the current evidence highlighting the clinical relevance and utility of tumor-infiltrating lymphocytes in breast cancer. Retrospective and prospective studies have shown that the presence of tumor-infiltrating lymphocytes is a prognostic marker for higher responses to neoadjuvant chemotherapy and better survival, particularly in triple negative and HER2-positive early breast cancer. Further work is required to determine the immune subsets important in this response and to discover ways of encouraging immune infiltrate in tumor-infiltrating lymphocytes-negative patients.
Literature
1.
Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331:1565–70.PubMed
2.
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.PubMedPubMedCentral
3.
Andre F, Dieci MV, Dubsky P, Sotiriou C, Curigliano G, Denkert C, et al. Molecular pathways: involvement of immune pathways in the therapeutic response and outcome in breast cancer. Clin Cancer Res. 2013;19:28–33.PubMed
4.
Caras I, Grigorescu A, Stavaru C, Radu DL, Mogos I, Szegli G, et al. Evidence for immune defects in breast and lung cancer patients. Cancer Immunol Immunother. 2004;53:1146–52.PubMed
5.
Monjazeb AM, Zamora AE, Grossenbacher SK, Mirsoian A, Sckisel GD, Murphy WJ. Immunoediting and antigen loss: overcoming the Achilles heel of immunotherapy with antigen non-specific therapies. Front Oncol. 2013;3:197.PubMedPubMedCentral
6.
Enderling H, Hlatky L, Hahnfeldt P. Immunoediting: evidence of the multifaceted role of the immune system in self-metastatic tumor growth. Theor Biol Med Model. 2012;9:31.PubMedPubMedCentral
7.
Vesely MD, Schreiber RD. Cancer immunoediting: antigens, mechanisms, and implications to cancer immunotherapy. Ann N Y Acad Sci. 2013;1284:1–5.PubMedPubMedCentral
8.
Quezada SA, Peggs KS, Simpson TR, Allison JP. Shifting the equilibrium in cancer immunoediting: from tumor tolerance to eradication. Immunol Rev. 2011;241:104–18.PubMedPubMedCentral
9.
Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 2002;3:991–8.PubMed
10.
O’Sullivan T, Saddawi-Konefka R, Vermi W, Koebel CM, Arthur C, White JM, et al. Cancer immunoediting by the innate immune system in the absence of adaptive immunity. J Exp Med. 2012;209:1869–82.PubMedPubMedCentral
11.
Emens LA. Breast cancer immunobiology driving immunotherapy: vaccines and immune checkpoint blockade. Expert Rev Anticancer Ther. 2012;12:1597–611.PubMedPubMedCentral
12.
13.
Wolchok JD, Chan TA. Cancer: antitumour immunity gets a boost. Nature. 2014;515:496–8.PubMed
14.
van Elsas A, Hurwitz AA, Allison JP. Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J Exp Med. 1999;190:355–66.PubMedPubMedCentral
15.
Fan X, Quezada SA, Sepulveda MA, Sharma P, Allison JP. Engagement of the ICOS pathway markedly enhances efficacy of CTLA-4 blockade in cancer immunotherapy. J Exp Med. 2014;211:715–25.PubMedPubMedCentral
16.
Kim K, Skora AD, Li Z, Liu Q, Tam AJ, Blosser RL, et al. Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. Proc Natl Acad Sci U S A. 2014;111:11774–9.PubMedPubMedCentral
17.
Pentcheva-Hoang T, Simpson TR, Montalvo-Ortiz W, Allison JP. Cytotoxic T lymphocyte antigen-4 blockade enhances antitumor immunity by stimulating melanoma-specific T-cell motility. Cancer Immunol Res. 2014;2:970–80.PubMed
18.
Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28:3167–75.PubMedPubMedCentral
19.
Wolchok JD, Neyns B, Linette G, Negrier S, Lutzky J, Thomas L, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11:155–64.PubMed
20.
21.
Beavis PA, Divisekera U, Paget C, Chow MT, John LB, Devaud C, et al. Blockade of A2A receptors potently suppresses the metastasis of CD73+ tumors. Proc Natl Acad Sci U S A. 2013;110:14711–6.PubMedPubMedCentral
22.
Beavis PA, Milenkovski N, Henderson MA, John LB, Allard B, Loi S, et al. Adenosine receptor 2A blockade increases the efficacy of anti-PD-1 through enhanced antitumor t-cell responses. Cancer Immunol Res. 2015;3:506–17.PubMed
23.
Beavis PA, Stagg J, Darcy PK, Smyth MJ. CD73: a potent suppressor of antitumor immune responses. Trends Immunol. 2012;33:231–7.PubMed
24.
Waickman AT, Alme A, Senaldi L, Zarek PE, Horton M, Powell JD. Enhancement of tumor immunotherapy by deletion of the A2A adenosine receptor. Cancer Immunol Immunother. 2012;61:917–26.PubMed
25.
Ohta A, Gorelik E, Prasad SJ, Ronchese F, Lukashev D, Wong MK, et al. A2A adenosine receptor protects tumors from antitumor T cells. Proc Natl Acad Sci U S A. 2006;103:13132–7.PubMedPubMedCentral
26.
Nishikawa H, Sakaguchi S. Regulatory T cells in cancer immunotherapy. Curr Opin Immunol. 2014;27:1–7.PubMed
27.
Zheng X, Koropatnick J, Chen D, Velenosi T, Ling H, Zhang X, et al. Silencing IDO in dendritic cells: a novel approach to enhance cancer immunotherapy in a murine breast cancer model. Int J Cancer. 2013;132:967–77.PubMed
28.
Holmgaard RB, Zamarin D, Munn DH, Wolchok JD, Allison JP. Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. J Exp Med. 2013;210:1389–402.PubMedPubMedCentral
29.
Holtzhausen A, Zhao F, Evans KS, Hanks BA. Early carcinogenesis involves the establishment of immune privilege via intrinsic and extrinsic regulation of indoleamine 2,3-dioxygenase-1: translational implications in cancer immunotherapy. Front Immunol. 2014;5:438.PubMedPubMedCentral
30.
Platten M, von Knebel DN, Oezen I, Wick W, Ochs K. Cancer immunotherapy by targeting IDO1/TDO and their downstream effectors. Front Immunol. 2014;5:673.PubMed
31.
Wang Z, Shi X, Li Y, Fan J, Zeng X, Xian Z, et al. Blocking autophagy enhanced cytotoxicity induced by recombinant human arginase in triple-negative breast cancer cells. Cell Death Dis. 2014;5:e1563.PubMedPubMedCentral
32.
Bedoya AM, Tate DJ, Baena A, Cordoba CM, Borrero M, Pareja R, et al. Immunosuppression in cervical cancer with special reference to arginase activity. Gynecol Oncol. 2014;135:74–80.PubMed
33.
Vasquez-Dunddel D, Pan F, Zeng Q, Gorbounov M, Albesiano E, Fu J, et al. STAT3 regulates arginase-I in myeloid-derived suppressor cells from cancer patients. J Clin Invest. 2013;123:1580–9.PubMedPubMedCentral
34.
35.
Forghani P, Khorramizadeh MR, Waller EK. Silibinin inhibits accumulation of myeloid-derived suppressor cells and tumor growth of murine breast cancer. Cancer Med. 2014;3:215–24.PubMedPubMedCentral
36.
Markowitz J, Wesolowski R, Papenfuss T, Brooks TR, Carson 3rd WE. Myeloid-derived suppressor cells in breast cancer. Breast Cancer Res Treat. 2013;140:13–21.PubMedPubMedCentral
37.
Ono M, Tsuda H, Shimizu C, Yamamoto S, Shibata T, Yamamoto H, et al. Tumor-infiltrating lymphocytes are correlated with response to neoadjuvant chemotherapy in triple-negative breast cancer. Breast Cancer Res Treat. 2012;132:793–805.PubMed
38.
West NR, Milne K, Truong PT, Macpherson N, Nelson BH, Watson PH. Tumor-infiltrating lymphocytes predict response to anthracycline-based chemotherapy in estrogen receptor-negative breast cancer. Breast Cancer Res. 2011;13:R126.PubMedPubMedCentral
39.
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;31:860–7.PubMed
40.
Wimberly H, Brown JR, Schalper KA, Haack H, Silver MR, Nixon C, et al. PD-L1 expression correlates with tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy in breast cancer. Cancer Immunol Res. 2014;3:326–32.PubMedPubMedCentral
41.
Denkert C, von Minckwitz G, Brase JC, Sinn BV, Gade S, Kronenwett R, 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;33:983–91.PubMed
42.
Ghiringhelli F, Larmonier N, Schmitt E, Parcellier A, Cathelin D, Garrido C, et al. CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. Eur J Immunol. 2004;34:336–44.PubMed
43.
Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G. Immunological aspects of cancer chemotherapy. Nat Rev Immunol. 2008;8:59–73.PubMed
44.
Ghiringhelli F, Apetoh L. The interplay between the immune system and chemotherapy: emerging methods for optimizing therapy. Expert Rev Clin Immunol. 2014;10:19–30.PubMed
45.
Ghiringhelli F, Apetoh L, Tesniere A, Aymeric L, Ma Y, Ortiz C, et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nat Med. 2009;15:1170–8.PubMed
46.
Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A, et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med. 2007;13:1050–9.PubMed
47.
Nowak AK, Robinson BW, Lake RA. Gemcitabine exerts a selective effect on the humoral immune response: implications for combination chemo-immunotherapy. Cancer Res. 2002;62:2353–8.PubMed
48.
Tongu M, Harashima N, Monma H, Inao T, Yamada T, Kawauchi H, et al. Metronomic chemotherapy with low-dose cyclophosphamide plus gemcitabine can induce anti-tumor T cell immunity in vivo. Cancer Immunol Immunother. 2013;62:383–91.PubMed
49.
Homma Y, Taniguchi K, Nakazawa M, Matsuyama R, Mori R, Takeda K, et al. Changes in the immune cell population and cell proliferation in peripheral blood after gemcitabine-based chemotherapy for pancreatic cancer. Clin Transl Oncol. 2014;16:330–5.PubMed
50.
Mozaffari F, Lindemalm C, Choudhury A, Granstam-Bjorneklett H, Lekander M, Nilsson B, et al. Systemic immune effects of adjuvant chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide and/or radiotherapy in breast cancer: a longitudinal study. Cancer Immunol Immunother. 2009;58:111–20.PubMed
51.
Lutsiak ME, Semnani RT, De Pascalis R, Kashmiri SV, Schlom J, Sabzevari H. Inhibition of CD4(+)25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood. 2005;105:2862–8.PubMed
52.
Zhu Y, Liu N, Xiong SD, Zheng YJ, Chu YW. CD4+Foxp3+ regulatory T-cell impairment by paclitaxel is independent of toll-like receptor 4. Scand J Immunol. 2011;73:301–8.PubMed
53.
Machiels JP, Reilly RT, Emens LA, Ercolini AM, Lei RY, Weintraub D, et al. Cyclophosphamide, doxorubicin, and paclitaxel enhance the antitumor immune response of granulocyte/macrophage-colony stimulating factor-secreting whole-cell vaccines in HER-2/neu tolerized mice. Cancer Res. 2001;61:3689–97.PubMed
54.
Park JY, Jang MJ, Chung YH, Kim KY, Kim SS, Lee WB, et al. Doxorubicin enhances CD4(+) T-cell immune responses by inducing expression of CD40 ligand and 4-1BB. Int Immunopharmacol. 2009;9:1530–9.PubMed
55.
Hannesdottir L, Tymoszuk P, Parajuli N, Wasmer MH, Philipp S, Daschil N, et al. Lapatinib and doxorubicin enhance the Stat1-dependent antitumor immune response. Eur J Immunol. 2013;43:2718–29.PubMed
56.
Nowak AK, Lake RA, Marzo AL, Scott B, Heath WR, Collins EJ, et al. Induction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing host tumor-specific CD8 T cells. J Immunol. 2003;170:4905–13.PubMed
57.
Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Annu Rev Immunol. 2013;31:51–72.PubMed
58.
Menard S, Tomasic G, Casalini P, Balsari A, Pilotti S, Cascinelli N, et al. Lymphoid infiltration as a prognostic variable for early-onset breast carcinomas. Clin Cancer Res. 1997;3:817–9.PubMed
59.
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;28:105–13.PubMed
60.
Ladoire S, Arnould L, Apetoh L, Coudert B, Martin F, Chauffert B, et al. Pathologic complete response to neoadjuvant chemotherapy of breast carcinoma is associated with the disappearance of tumor-infiltrating foxp3+ regulatory T cells. Clin Cancer Res. 2008;14:2413–20.PubMed
61.
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;30:1996–2004.PubMed
62.
Yu H, Yang J, Jiao S, Li Y, Zhang W, Wang J. T-box transcription factor 21 expression in breast cancer and its relationship with prognosis. Int J Clin Exp Pathol. 2014;7:6906–13.PubMedPubMedCentral
63.
Issa-Nummer Y, Darb-Esfahani S, Loibl S, Kunz G, Nekljudova V, Schrader I, et al. Prospective validation of immunological infiltrate for prediction of response to neoadjuvant chemotherapy in HER2-negative breast cancer--a substudy of the neoadjuvant GeparQuinto trial. PLoS One. 2013;8:e79775.PubMedPubMedCentral
64.
Dieci MV, Criscitiello C, Goubar A, Viale G, Conte P, Guarneri V, et al. Prognostic value of tumor-infiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: a retrospective multicenter study. Ann Oncol. 2014;25:611–8.PubMedPubMedCentral
65.
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;25:1544–50.PubMed
66.
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;32:2959–66.PubMedPubMedCentral
67.
Gennari R, Menard S, Fagnoni F, Ponchio L, Scelsi M, Tagliabue E, et al. Pilot study of the mechanism of action of preoperative trastuzumab in patients with primary operable breast tumors overexpressing HER2. Clin Cancer Res. 2004;10:5650–5.PubMed
68.
Salgado R, Denkert C, Campbell C, Savas P, Nucifero P, Aura C, et al. Tumor-infiltrating lymphocytes and associations with pathological complete response and event-free survival in HER2-positive early stage breast cancer treated with lapatinib and trastuzumab. JAMA Oncol. 2015;1:448–54.PubMed
69.
Arnould L, Gelly M, Penault-Llorca F, Benoit L, Bonnetain F, Migeon C, et al. Trastuzumab-based treatment of HER2-positive breast cancer: an antibody-dependent cellular cytotoxicity mechanism? Br J Cancer. 2006;94:259–67.PubMedPubMedCentral
70.
Bianchini G, Gianni L. The immune system and response to HER2-targeted treatment in breast cancer. Lancet Oncol. 2014;15:e58–68.PubMed
71.
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;136:107–16.PubMed
72.
Seo AN, Lee HJ, Kim EJ, Kim HJ, Jang MH, Lee HE, et al. Tumour-infiltrating CD8+ lymphocytes as an independent predictive factor for pathological complete response to primary systemic therapy in breast cancer. Br J Cancer. 2013;109:2705–13.PubMedPubMedCentral
73.
Lee HJ, Seo JY, Ahn JH, Ahn SH, Gong G. Tumor-associated lymphocytes predict response to neoadjuvant chemotherapy in breast cancer patients. J Breast Cancer. 2013;16:32–9.PubMedPubMedCentral
74.
Brown JR, Wimberly H, Lannin DR, Nixon C, Rimm DL, Bossuyt V. Multiplexed quantitative analysis of CD3, CD8, and CD20 predicts response to neoadjuvant chemotherapy in breast cancer. Clin Cancer Res. 2014;20:5995–6005.PubMedPubMedCentral
75.
Mahmoud S, Paish E, Powe D, Macmillan R, Grainge M, Lee A, et al. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin Oncol. 2011;29:1949–55.PubMed
76.
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;108:155–62.PubMed
77.
Aruga T, Suzuki E, Saji S, Horiguchi S, Horiguchi K, Sekine S, et al. A low number of tumor-infiltrating FOXP3-positive cells during primary systemic chemotherapy correlates with favorable anti-tumor response in patients with breast cancer. Oncol Rep. 2009;22:273–8.PubMed
78.
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;224:389–400.PubMed
79.
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;135:459–67.PubMed
80.
Ruffell B, Au A, Rugo HS, Esserman LJ, Hwang ES, Coussens LM. Leukocyte composition of human breast cancer. Proc Natl Acad Sci U S A. 2012;109:2796–801.PubMed
81.
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;123:2873–92.PubMedPubMedCentral
82.
Ma C, Zhang Q, Ye J, Wang F, Zhang Y, Wevers E, et al. Tumor-infiltrating gammadelta T lymphocytes predict clinical outcome in human breast cancer. J Immunol. 2012;189:5029–36.PubMedPubMedCentral
83.
Mattarollo SR, Kenna T, Nieda M, Nicol AJ. Chemotherapy and zoledronate sensitize solid tumour cells to Vgamma9Vdelta2 T cell cytotoxicity. Cancer Immunol Immunother. 2007;56:1285–97.PubMed
84.
Kobayashi H, Tanaka Y, Yagi J, Osaka Y, Nakazawa H, Uchiyama T, et al. Safety profile and anti-tumor effects of adoptive immunotherapy using gamma-delta T cells against advanced renal cell carcinoma: a pilot study. Cancer Immunol Immunother. 2007;56:469–76.PubMed
85.
Yang L, Qi Y, Hu J, Tang L, Zhao S, Shan B. Expression of Th17 cells in breast cancer tissue and its association with clinical parameters. Cell Biochem Biophys. 2012;62:153–9.PubMed
86.
Verma C, Eremin JM, Robins A, Bennett AJ, Cowley GP, El-Sheemy MA, et al. Abnormal T regulatory cells (Tregs: FOXP3+, CTLA-4+), myeloid-derived suppressor cells (MDSCs: monocytic, granulocytic) and polarised T helper cell profiles (Th1, Th2, Th17) in women with large and locally advanced breast cancers undergoing neoadjuvant chemotherapy (NAC) and surgery: failure of abolition of abnormal treg profile with treatment and correlation of treg levels with pathological response to NAC. J Transl Med. 2013;11:16.PubMedPubMedCentral
87.
Demaria S, Volm MD, Shapiro RL, Yee HT, Oratz R, Formenti SC, et al. Development of tumor-infiltrating lymphocytes in breast cancer after neoadjuvant paclitaxel chemotherapy. Clin Cancer Res. 2001;7:3025–30.PubMed
88.
Ercolini AM, Ladle BH, Manning EA, Pfannenstiel LW, Armstrong TD, Machiels JP, et al. Recruitment of latent pools of high-avidity CD8(+) T cells to the antitumor immune response. J Exp Med. 2005;201:1591–602.PubMedPubMedCentral
89.
Simpson TR, Li F, Montalvo-Ortiz W, Sepulveda MA, Bergerhoff K, Arce F, et al. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J Exp Med. 2013;210:1695–710.PubMedPubMedCentral
90.
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;1:54–67.PubMedPubMedCentral
91.
Alistar A, Chou J, Nagalla S, Black M, DAgostino R, Miller L. Dual roles for immune metagenes in breast cancer prognosis and therapy prediction. Genome Med. 2014;6:80.PubMedPubMedCentral
92.
Schalper KA, Velcheti V, Carvajal D, Wimberly H, Brown J, Pusztai L, et al. In situ tumor PD-L1 mRNA expression is associated with increased TILs and better outcome in breast carcinomas. Clin Cancer Res. 2014;20:2773–82.PubMed
93.
Muenst S, Schaerli AR, Gao F, Daster S, Trella E, Droeser RA, et al. Expression of programmed death ligand 1 (PD-L1) is associated with poor prognosis in human breast cancer. Breast Cancer Res Treat. 2014;146:15–24.PubMedPubMedCentral
94.
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;139:667–76.PubMed
95.
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;63:395–406.PubMed
96.
Taube JM, Klein AP, Brahmer JR, Xu H, Pan X, Kim JH, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res. 2014;20:5064.PubMedPubMedCentral
97.
Rahbar R, Lin A, Ghazarian M, Yau HL, Paramathas S, Lang PA, et al. B7-h4 expression by nonhematopoietic cells in the tumor microenvironment promotes antitumor immunity. Cancer Immunol Res. 2015;3:184–95.PubMed
98.
Sica GL, Choi IH, Zhu G, Tamada K, Wang SD, Tamura H, et al. B7-H4, a molecule of the B7 family, negatively regulates T cell immunity. Immunity. 2003;18:849–61.PubMed
99.
Zang X, Loke P, Kim J, Murphy K, Waitz R, Allison JP. B7x: a widely expressed B7 family member that inhibits T cell activation. Proc Natl Acad Sci U S A. 2003;100:10388–92.PubMedPubMedCentral
100.
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.PubMedPubMedCentral
101.
Lesterhuis WJ, Salmons J, Nowak AK, Rozali EN, Khong A, Dick IM, et al. Synergistic effect of CTLA-4 blockade and cancer chemotherapy in the induction of anti-tumor immunity. PLoS One. 2013;8:e61895.PubMedPubMedCentral
102.
Verbrugge I, Hagekyriakou J, Sharp LL, Galli M, West A, McLaughlin NM, et al. Radiotherapy increases the permissiveness of established mammary tumors to rejection by immunomodulatory antibodies. Cancer Res. 2012;72:3163–74.PubMed
103.
Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati E, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015;520:373–7.PubMed
104.
Liu L, Mayes PA, Eastman S, Shi H, Yadavilli S, Zhang T, et al. The BRAF and MEK inhibitors dabrafenib and trametinib: effects on immune function and in combination with immunomodulatory antibodies targeting PD-1, PD-L1, and CTLA-4. Clin Cancer Res. 2015;21:1639.PubMed
105.
Callahan MK, Masters G, Pratilas CA, Ariyan C, Katz J, Kitano S, et al. Paradoxical activation of T cells via augmented ERK signaling mediated by a RAF inhibitor. Cancer Immunol Res. 2014;2:70–9.PubMed
106.
Lee SJ, Myers L, Muralimohan G, Dai J, Qiao Y, Li Z, et al. 4-1BB and OX40 dual costimulation synergistically stimulate primary specific CD8 T cells for robust effector function. J Immunol. 2004;173:3002–12.PubMed
107.
Gray JC, French RR, James S, Al-Shamkhani A, Johnson PW, Glennie MJ. Optimising anti-tumour CD8 T-cell responses using combinations of immunomodulatory antibodies. Eur J Immunol. 2008;38:2499–511.PubMed
108.
Morales-Kastresana A, Sanmamed MF, Rodriguez I, Palazon A, Martinez-Forero I, Labiano S, et al. Combined immunostimulatory monoclonal antibodies extend survival in an aggressive transgenic hepatocellular carcinoma mouse model. Clin Cancer Res. 2013;19:6151–62.PubMed
109.
Cuadros C, Dominguez AL, Lollini PL, Croft M, Mittler RS, Borgstrom P, et al. Vaccination with dendritic cells pulsed with apoptotic tumors in combination with anti-OX40 and anti-4-1BB monoclonal antibodies induces T cell-mediated protective immunity in Her-2/neu transgenic mice. Int J Cancer. 2005;116:934–43.PubMed
110.
Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, et al. Patterns of somatic mutation in human cancer genomes. Nature. 2007;446:153–8.PubMedPubMedCentral
111.
Krauthammer M, Kong Y, Ha BH, Evans P, Bacchiocchi A, McCusker JP, et al. Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nat Genet. 2012;44:1006–14.PubMedPubMedCentral
112.
Wood LD, Parsons DW, Jones S, Lin J, Sjoblom T, Leary RJ, et al. The genomic landscapes of human breast and colorectal cancers. Science. 2007;318:1108–13.PubMed
113.
Marshall NA, Galvin KC, Corcoran AM, Boon L, Higgs R, Mills KH. Immunotherapy with PI3K inhibitor and Toll-like receptor agonist induces IFN-gamma+IL-17+ polyfunctional T cells that mediate rejection of murine tumors. Cancer Res. 2012;72:581–91.PubMed
114.
Dudley ME, Gross CA, Somerville RP, Hong Y, Schaub NP, Rosati SF, et al. Randomized selection design trial evaluating CD8+−enriched versus unselected tumor-infiltrating lymphocytes for adoptive cell therapy for patients with melanoma. J Clin Oncol. 2013;31:2152–9.PubMedPubMedCentral
115.
Chacon JA, Wu RC, Sukhumalchandra P, Molldrem JJ, Sarnaik A, Pilon-Thomas S, et al. Co-stimulation through 4-1BB/CD137 improves the expansion and function of CD8(+) melanoma tumor-infiltrating lymphocytes for adoptive T-cell therapy. PLoS One. 2013;8:e60031.PubMedPubMedCentral
116.
Kodumudi KN, Weber A, Sarnaik AA, Pilon-Thomas S. Blockade of myeloid-derived suppressor cells after induction of lymphopenia improves adoptive T cell therapy in a murine model of melanoma. J Immunol. 2012;189:5147–54.PubMedPubMedCentral
117.
Radvanyi LG, Bernatchez C, Zhang M, Fox PS, Miller P, Chacon J, et al. Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients. Clin Cancer Res. 2012;18:6758–70.PubMedPubMedCentral
118.
Kershaw MH, Westwood JA, Darcy PK. Gene-engineered T cells for cancer therapy. Nat Rev Cancer. 2013;13:525–41.PubMed
119.
Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371:1507–17.PubMedPubMedCentral
120.
Koya RC, Mok S, Otte N, Blacketor KJ, Comin-Anduix B, Tumeh PC, et al. BRAF inhibitor vemurafenib improves the antitumor activity of adoptive cell immunotherapy. Cancer Res. 2012;72:3928–37.PubMedPubMedCentral
121.
John LB, Devaud C, Duong CP, Yong CS, Beavis PA, Haynes NM, et al. Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells. Clin Cancer Res. 2013;19:5636–46.PubMed
122.
Ahmed N, Brawley VS, Hegde M, Robertson C, Ghazi A, Gerken C, et al. Human epidermal growth factor receptor 2 (HER2)-specific chimeric antigen receptor-modified T cells for the immunotherapy of HER2-positive sarcoma. J Clin Oncol. 2015;33:1688.PubMedPubMedCentral
123.
Ishikawa T, Adachi S, Okayama T, Kokura S, Mizushima K, Doi T, et al. Cytotoxic T lymphocyte-associated antigen 4 inhibition increases the antitumor activity of adoptive T-cell therapy when carried out with naive rather than differentiated T cells. Oncol Rep. 2015;33:2545.PubMed
124.
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;26:259–71.PubMed
125.
Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;384:164–72.PubMed
126.
Ko HJ, Kim YJ, Kim YS, Chang WS, Ko SY, Chang SY, et al. A combination of chemoimmunotherapies can efficiently break self-tolerance and induce antitumor immunity in a tolerogenic murine tumor model. Cancer Res. 2007;67:7477–86.PubMed
127.
Fridlender ZG, Sun J, Singhal S, Kapoor V, Cheng G, Suzuki E, et al. Chemotherapy delivered after viral immunogene therapy augments antitumor efficacy via multiple immune-mediated mechanisms. Mol Ther. 2010;18:1947–59.PubMedPubMedCentral
128.
Suzuki E, Kapoor V, Jassar AS, Kaiser LR, Albelda SM. Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res. 2005;11:6713–21.PubMed
129.
Schiavoni G, Sistigu A, Valentini M, Mattei F, Sestili P, Spadaro F, et al. Cyclophosphamide synergizes with type I interferons through systemic dendritic cell reactivation and induction of immunogenic tumor apoptosis. Cancer Res. 2011;71:768–78.PubMed
130.
Xu W, Cai J, Li S, Zhang H, Han J, Wen M, et al. Improving the in vivo persistence, distribution and function of cytotoxic T lymphocytes by inhibiting the tumor immunosuppressive microenvironment. Scand J Immunol. 2013;78:50–60.PubMed
131.
Umansky V, Sevko A. Overcoming immunosuppression in the melanoma microenvironment induced by chronic inflammation. Cancer Immunol Immunother. 2012;61:275–82.PubMed
132.
Zhang L, Dermawan K, Jin M, Liu R, Zheng H, Xu L, et al. Differential impairment of regulatory T cells rather than effector T cells by paclitaxel-based chemotherapy. Clin Immunol. 2008;129:219–29.PubMed
133.
Ma Y, Adjemian S, Mattarollo SR, Yamazaki T, Aymeric L, Yang H, et al. Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells. Immunity. 2013;38:729–41.PubMed
134.
Alizadeh D, Trad M, Hanke NT, Larmonier CB, Janikashvili N, Bonnotte B, et al. Doxorubicin eliminates myeloid-derived suppressor cells and enhances the efficacy of adoptive T-cell transfer in breast cancer. Cancer Res. 2014;74:104–18.PubMed
135.
Tesniere A, Schlemmer F, Boige V, Kepp O, Martins I, Ghiringhelli F, et al. Immunogenic death of colon cancer cells treated with oxaliplatin. Oncogene. 2010;29:482–91.PubMed
136.
Kang TH, Mao CP, Lee SY, Chen A, Lee JH, Kim TW, et al. Chemotherapy acts as an adjuvant to convert the tumor microenvironment into a highly permissive state for vaccination-induced antitumor immunity. Cancer Res. 2013;73:2493–504.PubMedPubMedCentral
137.
Guo ZS, Hong JA, Irvine KR, Chen GA, Spiess PJ, Liu Y, et al. De novo induction of a cancer/testis antigen by 5-aza-2′-deoxycytidine augments adoptive immunotherapy in a murine tumor model. Cancer Res. 2006;66:1105–13.PubMedPubMedCentral
138.
Mikyskova R, Indrova M, Vlkova V, Bieblova J, Simova J, Parackova Z, et al. DNA demethylating agent 5-azacytidine inhibits myeloid-derived suppressor cells induced by tumor growth and cyclophosphamide treatment. J Leukoc Biol. 2014; in press.
139.
Hornychova H, Melichar B, Tomsova M, Mergancova J, Urminska H, Ryska A. Tumor-infiltrating lymphocytes predict response to neoadjuvant chemotherapy in patients with breast carcinoma. Cancer Invest. 2008;26:1024–31.PubMed
140.
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:R48.PubMedPubMedCentral
141.
Yamaguchi R, Tanaka M, Yano A, Tse GM, Yamaguchi M, Koura K, et al. Tumor-infiltrating lymphocytes are important pathologic predictors for neoadjuvant chemotherapy in patients with breast cancer. Hum Pathol. 2012;43:1688–94.PubMed
142.
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;25:1536–43.PubMed
143.
Nabholtz JM, Abrial C, Mouret-Reynier MA, Dauplat MM, Weber B, Gligorov J, et al. Multicentric neoadjuvant phase II study of panitumumab combined with an anthracycline/taxane-based chemotherapy in operable triple-negative breast cancer: identification of biologically defined signatures predicting treatment impact. Ann Oncol. 2014;25:1570–7.PubMed
Metadata
Title
Relevance of tumor-infiltrating lymphocytes in breast cancer
Authors
Sathana Dushyanthen
Paul A. Beavis
Peter Savas
Zhi Ling Teo
Chenhao Zhou
Mariam Mansour
Phillip K. Darcy
Sherene Loi
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2015
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-015-0431-3

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