nach oben

Erschienen in:

09.03.2016 | Preclinical study

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

verfasst von: Hirofumi Matsumoto, Aye Aye Thike, Huihua Li, Joe Yeong, Si-lin Koo, Rebecca Alexandra Dent, Puay Hoon Tan, Jabed Iqbal

Erschienen in: Breast Cancer Research and Treatment | Ausgabe 2/2016

Einloggen, um Zugang zu erhalten

Abstract

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.

Reis-Filho JS, Tutt ANJ (2008) Triple negative tumours: a critical review. Histopathology 52:108–118CrossRefPubMed

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

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 121:2750–2767CrossRefPubMedPubMedCentral

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 13:1050–1059CrossRefPubMed

Zitvogel L, Apetoh L, Ghiringhelli F, André F, Tesniere A, Kroemer G (2008) The anticancer immune response: indispensable for therapeutic success. J Clin Invest 118:1991–2001CrossRefPubMedPubMedCentral

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 28:105–113CrossRefPubMed

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

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

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–e31CrossRefPubMed

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 94:275–280CrossRefPubMedPubMedCentral

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 29:1949–1955CrossRefPubMed

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:R48CrossRefPubMedPubMedCentral

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 23:123–133CrossRefPubMed

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 139:381–390CrossRefPubMed

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 1:625–632PubMedPubMedCentral

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 16:432CrossRefPubMedPubMedCentral

17.

Lee S, Cho EY, Park YH, Ahn JS, Im YH (2013) Prognostic impact of foxp3 expression in triple-negative breast cancer. Acta Oncol 52:73–81CrossRefPubMed

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 48:692–701CrossRefPubMed

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 16:488CrossRefPubMedPubMedCentral

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 6:17462–17478CrossRefPubMedPubMedCentral

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 33:1298–1299CrossRefPubMed

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:e115103CrossRefPubMedPubMedCentral

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 86:231–245CrossRefPubMed

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 10:604CrossRefPubMedPubMedCentral

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 109:2705–2713CrossRefPubMedPubMedCentral

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 45:1780–1787CrossRefPubMed

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:e17876CrossRefPubMedPubMedCentral

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 22:98–103CrossRefPubMed

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:e38783CrossRefPubMedPubMedCentral

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 109:2796–2801CrossRefPubMedPubMedCentral

36.

Scandiuzzi L, Ghosh K, Zang X (2011) T cell costimulation and coinhibition: genetics and disease. Discov Med 12:119–128PubMedPubMedCentral

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 8:190–198CrossRefPubMedPubMedCentral

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 121:751–758CrossRefPubMed

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 3:177–189PubMedPubMedCentral

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 3:988–997CrossRefPubMedPubMedCentral

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 2:571–582CrossRefPubMedPubMedCentral

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 123:2873–2892CrossRefPubMedPubMedCentral

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 168:5954–5958CrossRefPubMed

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 58:139–149CrossRefPubMed

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:R126CrossRefPubMedPubMedCentral

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 26:259–271CrossRefPubMed

Titel: Increased CD4 and CD8-positive T cell infiltrate signifies good prognosis in a subset of triple-negative breast cancer
verfasst von: Hirofumi Matsumoto
Aye Aye Thike
Huihua Li
Joe Yeong
Si-lin Koo
Rebecca Alexandra Dent
Puay Hoon Tan
Jabed Iqbal
Publikationsdatum: 09.03.2016
Verlag: Springer US
Erschienen in: Breast Cancer Research and Treatment / Ausgabe 2/2016
Print ISSN: 0167-6806
Elektronische ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-016-3743-x

Neu im Fachgebiet Onkologie

19.04.2024 | EAU 2024 | Kongressbericht | Nachrichten

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

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

Abstract

Neu im Fachgebiet Onkologie

Prostatakarzinom: EU initiiert neues Screeningkonzept

Blasenkarzinom – Biomarker statt Zytologie?

Stereotaktische Radiatio schlägt konventionelle Bestrahlung

Adjuvante Brustkrebstherapie: Doppelt hält besser

Update Onkologie

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 2/2016

The clinical value of HER-2 overexpression and PIK3CA mutations in the older breast cancer population: a FOCUS study analysis

A non-randomized dose-escalation Phase I trial of a protein-based immunotherapeutic for the treatment of breast cancer patients with HER2-overexpressing tumors

Effect of ALDH1 on prognosis and chemoresistance by breast cancer subtype

Developmental signaling pathways regulating mammary stem cells and contributing to the etiology of triple-negative breast cancer

A novel gene expression signature for bone metastasis in breast carcinomas

A comparison of toxicity profiles between the lower and standard dose capecitabine in breast cancer: a systematic review and meta-analysis

Neu im Fachgebiet Onkologie

Prostatakarzinom: EU initiiert neues Screeningkonzept

Blasenkarzinom – Biomarker statt Zytologie?

Stereotaktische Radiatio schlägt konventionelle Bestrahlung

Adjuvante Brustkrebstherapie: Doppelt hält besser

Update Onkologie