Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 2/2016

01-04-2016 | Preclinical study

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

Published in: Breast Cancer Research and Treatment | Issue 2/2016

Login to get access

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.
Literature
1.
Reis-Filho JS, Tutt ANJ (2008) Triple negative tumours: a critical review. Histopathology 52:108–118CrossRefPubMed
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 121:2750–2767CrossRefPubMedPubMedCentral
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 13:1050–1059CrossRefPubMed
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 118:1991–2001CrossRefPubMedPubMedCentral
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 28:105–113CrossRefPubMed
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–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.
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
Metadata
Title
Increased CD4 and CD8-positive T cell infiltrate signifies good prognosis in a subset of triple-negative breast cancer
Publication date
01-04-2016
Published in
Breast Cancer Research and Treatment / Issue 2/2016
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-016-3743-x

Other articles of this Issue 2/2016

Breast Cancer Research and Treatment 2/2016 Go to the issue

Clinical trial

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

Preclinical study

Equivalence of MammaPrint array types in clinical trials and diagnostics

Epidemiology

Investigating racial disparities in use of NK1 receptor antagonists to prevent chemotherapy-induced nausea and vomiting among women with breast cancer

Epidemiology

Very low local recurrence rates after breast-conserving therapy: analysis of 8485 patients treated over a 28-year period

Epidemiology

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

Erratum

Erratum to: RAGE-binding S100A8/A9 promotes the migration and invasion of human breast cancer cells through actin polymerization and epithelial–mesenchymal transition
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits