Increased CD4 and CD8-positive T cell infiltrate signifies good prognosis in a subset of triple-negative breast cancer

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• 作者：Hirofumi Matsumoto ; Aye Aye Thike ; Huihua Li…
• 关键词：CD4 ; CD8 ; Triple ; negative breast cancer (TNBC) ; Lymphocytes ; Overall survival
• 刊名：Breast Cancer Research and Treatment
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：156
• 期：2
• 页码：237-247
• 全文大小：8,296 KB
• 参考文献：1.Reis-Filho JS, Tutt ANJ (2008) Triple negative tumours: a critical review. Histopathology 52:108–118CrossRef PubMed
  2.Criscitiello C, Azim HA, Schouten PC, Linn SC, Sotiriou C (2012) Understanding the biology of triple-negative breast cancer. Ann Oncol Suppl 6:vi13–vi18
  3.Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, Pietenpol JA (2011) Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 121:2750–2767CrossRef PubMed PubMedCentral
  4.Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A, Mignot G, Maiuri MC, Ullrich E, Saulnier P, Yang H, Amigorena S, Ryffel B, Barrat FJ, Saftig P, Levi F, Lidereau R, Nogues C, Mira JP, Chompret A, Joulin V, Clavel-Chapelon F, Bourhis J, André F, Delaloge S, Tursz T, Kroemer G, Zitvogel L (2007) Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 13:1050–1059CrossRef PubMed
  5.Zitvogel L, Apetoh L, Ghiringhelli F, André F, Tesniere A, Kroemer G (2008) The anticancer immune response: indispensable for therapeutic success. J Clin Invest 118:1991–2001CrossRef PubMed PubMedCentral
  6.Denkert C, Loibl S, Noske A, Roller M, Müller BM, Komor M, Budczies J, Darb-Esfahani S, Kronenwett R, Hanusch C, von Törne C, Weichert W, Engels K, Solbach C, Schrader I, Dietel M, von Minckwitz G (2010) Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol 28:105–113CrossRef PubMed
  7.Naito Y, Saito K, Shiiba K, Ohuchi A, Saigenji K, Nagura H, Ohtani H (1998) Cd8 + t cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res 58:3491–3494PubMed
  8.Schumacher K, Haensch W, Röefzaad C, Schlag PM (2001) Prognostic significance of activated cd8(+) t cell infiltrations within esophageal carcinomas. Cancer Res 61:3932–3936PubMed
  9.Fukunaga A, Miyamoto M, Cho Y, Murakami S, Kawarada Y, Oshikiri T, Kato K, Kurokawa T, Suzuoki M, Nakakubo Y, Hiraoka K, Itoh T, Morikawa T, Okushiba S, Kondo S, Katoh H (2004) Cd8 + tumor-infiltrating lymphocytes together with cd4 + tumor-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma. Pancreas 28:e26–e31CrossRef PubMed
  10.Hiraoka K, Miyamoto M, Cho Y, Suzuoki M, Oshikiri T, Nakakubo Y, Itoh T, Ohbuchi T, Kondo S, Katoh H (2006) Concurrent infiltration by cd8 + t cells and cd4 + t cells is a favourable prognostic factor in non-small-cell lung carcinoma. Br J Cancer 94:275–280CrossRef PubMed PubMedCentral
  11.Mahmoud SMA, Paish EC, Powe DG, Macmillan RD, Grainge MJ, Lee AHS, Ellis IO, Green AR (2011) Tumor-infiltrating cd8 + lymphocytes predict clinical outcome in breast cancer. J Clin Oncol 29:1949–1955CrossRef PubMed
  12.Liu S, Lachapelle J, Leung S, Gao D, Foulkes WD, Nielsen TO (2012) Cd8+ lymphocyte infiltration is an independent favorable prognostic indicator in basal-like breast cancer. Breast Cancer Res 14:R48CrossRef PubMed PubMedCentral
  13.Thike AA, Cheok PY, Jara-Lazaro AR, Tan B, Tan P, Tan PH (2010) Triple-negative breast cancer: clinicopathological characteristics and relationship with basal-like breast cancer. Mod Pathol 23:123–133CrossRef PubMed
  14.Lal A, Chan L, Devries S, Chin K, Scott GK, Benz CC, Chen YY, Waldman FM, Hwang ES (2013) Foxp3-positive regulatory t lymphocytes and epithelial foxp3 expression in synchronous normal, ductal carcinoma in situ, and invasive cancer of the breast. Breast Cancer Res Treat 139:381–390CrossRef PubMed
  15.Takenaka M, Seki N, Toh U, Hattori S, Kawahara A, Yamaguchi T, Koura K, Takahashi R, Otsuka H, Takahashi H, Iwakuma N, Nakagawa S, Fujii T, Sasada T, Yamaguchi R, Yano H, Shirouzu K, Kage M (2013) Foxp3 expression in tumor cells and tumor-infiltrating lymphocytes is associated with breast cancer prognosis. Mol Clin Oncol 1:625–632PubMed PubMedCentral
  16.Liu S, Foulkes W, Leung S, Gao D, Lau S, Kos Z, Nielsen T (2014) 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 16:432CrossRef PubMed PubMedCentral
  17.Lee S, Cho EY, Park YH, Ahn JS, Im YH (2013) Prognostic impact of foxp3 expression in triple-negative breast cancer. Acta Oncol 52:73–81CrossRef PubMed
  18.Lee AHS, Gillett CE, Ryder K, Fentiman IS, Miles DW, Millis RR (2006) Different patterns of inflammation and prognosis in invasive carcinoma of the breast. Histopathology 48:692–701CrossRef PubMed
  19.García-Martínez E, Gil G, Benito A, González-Billalabeitia E, Conesa M, García G, García-Garre E, Vicente V, Ayala D (2014) Tumor-infiltrating immune cell profiles and their change after neoadjuvant chemotherapy predict response and prognosis of breast cancer. Breast Cancer Res 16:488CrossRef PubMed PubMedCentral
  20.Huang Y, Ma C, Zhang Q, Ye J, Wang F, Zhang Y, Hunborg P, Varvares M, Hoft D, Hsueh E, Peng G (2015) Cd4 + and cd8 + t cells have opposing roles in breast cancer progression and outcome. Oncotarget 6:17462–17478CrossRef PubMed PubMedCentral
  21.Al-Hassan AA, Al-Ghurabi BH, Al-Karkhi IH (2012) Prognostic value of proinflammatory cytokines in breast cancer. J Biomol Res Ther 1:104
  22.Chen Z, Chen X, Zhou E, Chen G, Qian K, Wu X, Miao X, Tang Z (2014) Intratumoral cd8+ cytotoxic lymphocyte is a favorable prognostic marker in node-negative breast cancer. PLoS ONE 9:10
  23.Matkowski R, Gisterek I, Halon A, Lacko A, Szewczyk K, Staszek U, Pudelko M, Szynglarewicz B, Szelachowska J, Zolnierek A, Kornafel J (2009) The prognostic role of tumor-infiltrating cd4 and cd8 t lymphocytes in breast cancer. Anticancer Res 29:2445–2451PubMed
  24.Baker K, Lachapelle J, Zlobec I, Bismar TA, Terracciano L, Foulkes WD (2011) Prognostic significance of cd8 + t lymphocytes in breast cancer depends upon both oestrogen receptor status and histological grade. Histopathology 58:1107–1116PubMed
  25.Ocaña A, Diez-Gónzález L, Adrover E, Fernández-Aramburo A, Pandiella A, Amir E (2015) Tumor-infiltrating lymphocytes in breast cancer: ready for prime time. J Clin Oncol 33:1298–1299CrossRef PubMed
  26.Mao Y, Qu Q, Zhang Y, Liu J, Chen X, Shen K (2014) The value of tumor infiltrating lymphocytes (tils) for predicting response to neoadjuvant chemotherapy in breast cancer: a systematic review and meta-analysis. PLoS ONE 9:e115103CrossRef PubMed PubMedCentral
  27.Plos ONE Staff (2015) Correction: the value of tumor infiltrating lymphocytes (tils) for predicting response to neoadjuvant chemotherapy in breast cancer: a systematic review and meta-analysis. PLoS ONE 10:e0119243CrossRef
  28.Yu P, Fu YX (2006) Tumor-infiltrating t lymphocytes: friends or foes. Lab Invest 86:231–245CrossRef PubMed
  29.Teschendorff AE, Gomez S, Arenas A, El-Ashry D, Schmidt M, Gehrmann M, Caldas C (2010) Improved prognostic classification of breast cancer defined by antagonistic activation patterns of immune response pathway modules. BMC Cancer 10:604CrossRef PubMed PubMedCentral
  30.Seo AN, Lee HJ, Kim EJ, Kim HJ, Jang MH, Lee HE, Kim YJ, Kim JH, Park SY (2013) Tumour-infiltrating cd8 + lymphocytes as an independent predictive factor for pathological complete response to primary systemic therapy in breast cancer. Br J Cancer 109:2705–2713CrossRef PubMed PubMedCentral
  31.Rakha EA, Aleskandarany M, El-Sayed ME, Blamey RW, Elston CW, Ellis IO, Lee AHS (2009) The prognostic significance of inflammation and medullary histological type in invasive carcinoma of the breast. Eur J Cancer 45:1780–1787CrossRef PubMed
  32.Chen YT, Ross DS, Chiu R, Zhou XK, Chen YY, Lee P, Hoda SA, Simpson AJ, Old LJ, Caballero O, Neville AM (2011) Multiple cancer/testis antigens are preferentially expressed in hormone-receptor negative and high-grade breast cancers. PLoS ONE 6:e17876CrossRef PubMed PubMedCentral
  33.Curigliano G, Viale G, Ghioni M, Jungbluth AA, Bagnardi V, Spagnoli GC, Neville AM, Nolè F, Rotmensz N, Goldhirsch A (2011) Cancer-testis antigen expression in triple-negative breast cancer. Ann Oncol 22:98–103CrossRef PubMed
  34.Ademuyiwa FO, Bshara W, Attwood K, Morrison C, Edge SB, Karpf AR, James SA, Ambrosone CB, O’Connor TL, Levine EG, Miliotto A, Ritter E, Ritter G, Gnjatic S, Odunsi K (2012) Ny-eso-1 cancer testis antigen demonstrates high immunogenicity in triple negative breast cancer. PLoS ONE 7:e38783CrossRef PubMed PubMedCentral
  35.Ruffell B, Au A, Rugo HS, Esserman LJ, Hwang ES, Coussens LM (2012) Leukocyte composition of human breast cancer. Proc Natl Acad Sci U S A 109:2796–2801CrossRef PubMed PubMedCentral
  36.Scandiuzzi L, Ghosh K, Zang X (2011) T cell costimulation and coinhibition: genetics and disease. Discov Med 12:119–128PubMed PubMedCentral
  37.Ghebeh H, Mohammed S, Al-Omair A, Qattan A, Lehe C, Al-Qudaihi G, Elkum N, Alshabanah M, Bin Amer S, Tulbah A, Ajarim D, Al-Tweigeri T, Dermime S (2006) The b7-h1 (pd-l1) t lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltrating ductal carcinoma: correlation with important high-risk prognostic factors. Neoplasia 8:190–198CrossRef PubMed PubMedCentral
  38.Ghebeh H, Tulbah A, Mohammed S, Elkum N, Bin Amer SM, Al-Tweigeri T, Dermime S (2007) Expression of b7-h1 in breast cancer patients is strongly associated with high proliferative ki-67-expressing tumor cells. Int J Cancer 121:751–758CrossRef PubMed
  39.Tawara K, Oxford JT, Jorcyk CL (2011) Clinical significance of interleukin (il)-6 in cancer metastasis to bone: potential of anti-il-6 therapies. Cancer Manag Res 3:177–189PubMed PubMedCentral
  40.Perez R, Schally AV, Vidaurre I, Rincon R, Block NL, Rick FG (2012) Antagonists of growth hormone-releasing hormone suppress in vivo tumor growth and gene expression in triple negative breast cancers. Oncotarget 3:988–997CrossRef PubMed PubMedCentral
  41.Singh M, Ramos I, Asafu-Adjei D, Quispe-Tintaya W, Chandra D, Jahangir A, Zang X, Aggarwal BB, Gravekamp C (2013) Curcumin improves the therapeutic efficacy of listeria(at)-mage-b vaccine in correlation with improved t-cell responses in blood of a triple-negative breast cancer model 4t1. Cancer Med 2:571–582CrossRef PubMed PubMedCentral
  42.Gu-Trantien C, Loi S, Garaud S, Equeter C, Libin M, de Wind A, Ravoet M, Le Buanec H, Sibille C, Manfouo-Foutsop G, Veys I, Haibe-Kains B, Singhal SK, Michiels S, Rothé F, Salgado R, Duvillier H, Ignatiadis M, Desmedt C, Bron D, Larsimont D, Piccart M, Sotiriou C, Willard-Gallo K (2013) Cd4+ follicular helper t cell infiltration predicts breast cancer survival. J Clin Invest 123:2873–2892CrossRef PubMed PubMedCentral
  43.Appay V, Zaunders JJ, Papagno L, Sutton J, Jaramillo A, Waters A, Easterbrook P, Grey P, Smith D, McMichael AJ, Cooper DA, Rowland-Jones SL, Kelleher AD (2002) Characterization of cd4(+) ctls ex vivo. J Immunol 168:5954–5958CrossRef PubMed
  44.Fu J, Zhang Z, Zhou L, Qi Z, Xing S, Lv J, Shi J, Fu B, Liu Z, Zhang JY, Jin L, Zhao Y, Lau GKK, Zhao J, Wang FS (2013) Impairment of cd4+ cytotoxic t cells predicts poor survival and high recurrence rates in patients with hepatocellular carcinoma. Hepatology 58:139–149CrossRef PubMed
  45.West NR, Milne K, Truong PT, Macpherson N, Nelson BH, Watson PH (2011) Tumor-infiltrating lymphocytes predict response to anthracycline-based chemotherapy in estrogen receptor-negative breast cancer. Breast Cancer Res 13:R126CrossRef PubMed PubMedCentral
  46.Salgado R, Denkert C, Demaria S et al (2015) The evaluation of tumor-infiltrating lymphocytes (tils) in breast cancer: recommendations by an international tils working group 2014. Ann Oncol 26:259–271CrossRef PubMed
  
• 作者单位：Hirofumi Matsumoto (1)
  Aye Aye Thike (2)
  Huihua Li (3)
  Joe Yeong (2) (4)
  Si-lin Koo (5)
  Rebecca Alexandra Dent (5)
  Puay Hoon Tan (2)
  Jabed Iqbal (2)
  
  1. Department of Pathology, Ryukyu University Hospital, Okinawa, Japan
  2. Department of Pathology, Singapore General Hospital, 20 College Road, Academia, Level 10, Singapore, 169856, Singapore
  3. Division of Research, Singapore General Hospital, Singapore, Singapore
  4. Singapore Immunology Network, Agency of Science, Technology and Research, Singapore, Singapore
  5. Department of Medical Oncology, National Cancer Centre, Singapore, Singapore
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Oncology
  
• 出版者：Springer Netherlands
• ISSN：1573-7217

文摘

Tumour-infiltrating lymphocytes (TILs) signify immune response to tumour in a variety of cancers including breast cancer. However, earlier studies examining the clinical significance of TILs in breast cancers have generated mixed results. There are only a few that address the relationship between TILs and clinical outcomes in triple-negative breast cancers (TNBC). The aim of this study is to evaluate the clinical significance of TILs that express CD4 + and CD8 + , in TNBC. Immunohistochemical staining of CD4 and CD8 was performed on tissue microarrays of 164 cases of TNBC. TILs were counted separately as intratumoral when within the cancer cell nests (iTILs) and as stromal when within cancer stroma (sTILs). High CD8 + iTILs and sTILs, and CD4 + iTILs correlated with histologic grade. On Kaplan–Meier analysis, a significantly better survival rate was observed in high CD8 + iTIL (disease-free survival, DFS: P = 0.004, overall survival, OS: P = 0.02) and both high CD4 + iTILs (DFS: P = 0.025, OS: P = 0.023) and sTILs (DFS: P = 0.01, OS: P = 0.002). In multivariate analysis, CD8 + iTILs (DFS: P = 0.0095), CD4 + sTILs (DFS: P = 0.0084; OS: P = 0.0118), and CD4 high CD8 high CD8 iTILs (DFS: P = 0.0121; OS: P = 0.0329) and sTILs (DFS: P = 0.0295) showed significantly better survival outcomes. These results suggest that high levels of both CD8 + iTILs and CD4 + sTILs as well as CD4 high CD8 high iTILs and sTILs are independent prognostic factors in TNBC.