Top

Published in:

01-11-2011 | Epidemiology

CD8⁺ cytotoxic T cell and FOXP3⁺ regulatory T cell infiltration in relation to breast cancer survival and molecular subtypes

Authors: Fangfang Liu, Ronggang Lang, Jing Zhao, Xinmin Zhang, Gordon A. Pringle, Yu Fan, Dong Yin, Feng Gu, Zhi Yao, Li Fu

Published in: Breast Cancer Research and Treatment | Issue 2/2011

Abstract

The prognostic significance of tumor-associated FOXP3⁺ regulatory T cells (Tregs) and CD8⁺ cytotoxic T lymphocytes (CTLs) in invasive breast carcinomas is studied. Tregs and CTLs were assessed by immunohistochemistry in 1270 cases of invasive breast carcinoma for their associations with patient survival, histopathologic features, and molecular subtypes. Infiltrates of Tregs and CTLs were observed within tumor bed and in the tissue surrounding tumor. Within tumor bed, increased infiltration of Tregs and CTLs was significantly more common in those with unfavorable histologic features, including high histologic grade and negative ER and PR status. In addition, high density Treg infiltration was also associated with tumor HER2 overexpression, decreased overall survival (OS) and progression-free survival (PFS). In tissue surrounding tumor, in contrast, high CTL/Treg ratio was found to be significantly associated with improved OS and PFS. These prognostic associations were confirmed by multivariate analysis. Furthermore, the density of Treg infiltrates within tumors was inversely correlated with the prognosis of the molecular subtypes of tumors. The ratio of CTL/Treg infiltrates in the surrounding tissue was also significantly higher in luminal than non-luminal subtypes of carcinoma. The prognostic significances of Tregs and CTLs in breast carcinoma depend on their relative density and location. The density of intratumoral Treg infiltrates and the peritumoral CTL/Treg ratio are independent prognostic factors and correlated with the prognosis of the molecular subtypes of breast carcinoma, which may serve as potential target for stratifying immunotherapy to battle against the aggressive subtypes of breast carcinoma.

Galon J, Costes A, Sanchez-Cabo F et al (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313:1960–1964PubMedCrossRef

Parmiani G (2005) Tumor-infiltrating T-cells—friend or foe of neoplastic cells? N Engl J Med 353:2640–2641PubMedCrossRef

Chiou SH, Sheu BC, Chang WC, Huang SC, Ho HN (2005) Current concepts of tumor-infiltrating lymphocytes in human malignancies. J Reprod Immunol 67:35–50PubMedCrossRef

Yu P, Fu YX (2006) Tumor-infiltrating T lymphocytes: friends or foes? Lab Invest 86:231–245PubMedCrossRef

Unitt E, Rushbrook SM, Marshall A et al (2005) Compromised lymphocytes infiltrate hepatocellular carcinoma: the role of T-regulatory cells. Hepatology 41:722–730PubMedCrossRef

Guo XJ, Fan Y, Lang RG et al (2008) Tumor infiltrating lymphocytes differ in invasive micropapillary carcinoma and medullary carcinoma of breast. Mod Pathol 21:1101–1107PubMedCrossRef

Pages F, Berger A, Camus M et al (2005) Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 353:2654–2666PubMedCrossRef

Zhang L, Conejo-Garcia JR, Katsaros D et al (2003) Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 348:203–213PubMedCrossRef

Leong PP, Mohammad R, Ibrahim N et al (2006) Phenotyping of lymphocytes expressing regulatory and effector markers in infiltrating ductal carcinoma of the breast. Immunol Lett 102:229–236PubMedCrossRef

10.

Baxevanis CN, Dedoussis GV, Papadopoulos NG, Missitzis I, Stathopoulos GP, Papamichail M (1994) Tumor specific cytolysis by tumor infiltrating lymphocytes in breast cancer. Cancer 74:1275–1282PubMedCrossRef

11.

Curiel TJ (2007) Tregs and rethinking cancer immunotherapy. J Clin Invest 117:1167–1174PubMedCrossRef

12.

Zou W (2006) Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 6:295–307PubMedCrossRef

13.

Curiel TJ, Coukos G, Zou LH et al (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10:942–949PubMedCrossRef

14.

Annunziato F, Cosmi L, Liotta F et al (2002) Phenotype, localization, and mechanism of suppression of CD4(+)CD25(+) human thymocytes. J Exp Med 196:379–387PubMedCrossRef

15.

Xu L, Xu W, Jiang Z, Zhang F, Chu Y, Xiong S (2009) Depletion of CD4(+)CD25(high) regulatory T cells from tumor infiltrating lymphocytes predominantly induces Th1 type immune response in vivo which inhibits tumor growth in adoptive immunotherapy. Cancer Biol Ther 8:66–72PubMedCrossRef

16.

Sato E, Olson SH, Ahn J et al (2005) Intraepithelial CD8(+) tumor-infiltrating lymphocytes and a high CD8(+)/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA 102:18538–18543PubMedCrossRef

17.

Kobayashi N, Hiraoka N, Yamagami W et al (2007) FOXP3(+) regulatory T cells affect the development and progression of hepatocarcinogenesis. Clin Cancer Res 13:902–911PubMedCrossRef

18.

Gao Q, Qiu SJ, Fan J et al (2007) Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 25:2586–2593PubMedCrossRef

19.

Hiraoka N, Onozato K, Kosuge T, Hirohashi S (2006) Prevalence of FOXP3(+) regulatory T cells increases during the progression of pancreatic ductal adenocarcinorna and its premalignant lesions. Clin Cancer Res 12:5423–5434PubMedCrossRef

20.

Alvaro T, Lejeune M, Salvado MT et al (2005) Outcome in Hodgkin’s lymphoma can be predicted from the presence of accompanying cytotoxic and regulatory T cells. Clin Cancer Res 11:1467–1473PubMedCrossRef

21.

Dieu-Nosjean MC, Antoine M, Danel C et al (2008) Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J Clin Oncol 26:4410–4417PubMedCrossRef

22.

Salama P, Phillips M, Grieu F et al (2009) Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 27:186–192PubMedCrossRef

23.

Bates GJ, Fox SB, Han C et al (2006) Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol 24:5373–5380PubMedCrossRef

24.

Bohling SD, Allison KH (2008) Immunosuppressive regulatory T cells are associated with aggressive breast cancer phenotypes: a potential therapeutic target. Mod Pathol 21:1527–1532PubMedCrossRef

25.

Gobert M, Treilleux I, Bendriss-Vermare N et al (2009) 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 69:2000–2009PubMedCrossRef

26.

Elston CW, Ellis IO (1991) Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 19:403–410PubMedCrossRef

27.

Cheang MC, Chia SK, Voduc D et al (2009) Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst 101:736–750PubMedCrossRef

28.

Voduc KD, Cheang MC, Tyldesley S, Gelmon K, Nielsen TO, Kennecke H (2010) Breast cancer subtypes and the risk of local and regional relapse. J Clin Oncol 28:1684–1691PubMedCrossRef

29.

Grabenbauer GG, Lahmer G, Distel L, Niedobitek G (2006) Tumor-infiltrating cytotoxic T cells but not regulatory T cells predict outcome in anal squamous cell carcinoma. Clin Cancer Res 12:3355–3360PubMedCrossRef

30.

Nakano O, Sato M, Naito Y et al (2001) Proliferative activity of intratumoral CD8(+) T-lymphocytes as a prognostic factor in human renal cell carcinoma: clinicopathologic demonstration of antitumor immunity. Cancer Res 61:5132–5136PubMed

31.

La Rocca G, Anzalone R, Corrao S et al (2008) CD1a down-regulation in primary invasive ductal breast carcinoma may predict regional lymph node invasion and patient outcome. Histopathology 52:203–212PubMedCrossRef

32.

Matkowski R, Gisterek I, Halon A et al (2009) The prognostic role of tumor-infiltrating CD4 and CD8 T lymphocytes in breast cancer. Anticancer Res 29:2445–2451PubMed

Title: CD8+ cytotoxic T cell and FOXP3+ regulatory T cell infiltration in relation to breast cancer survival and molecular subtypes
Authors: Fangfang Liu
Ronggang Lang
Jing Zhao
Xinmin Zhang
Gordon A. Pringle
Yu Fan
Dong Yin
Feng Gu
Zhi Yao
Li Fu
Publication date: 01-11-2011
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 2/2011
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-011-1647-3

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

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2011

Association between polymorphisms of the renin–angiotensin system genes and breast cancer risk: a meta-analysis

COX-2 expression predicts worse breast cancer prognosis and does not modify the association with aspirin

CG0006, a novel histone deacetylase inhibitor, induces breast cancer cell death via histone-acetylation and chaperone-disrupting pathways independent of ER status

A retrospective study of breast cancer subtypes: the risk of relapse and the relations with treatments

Unmet supportive care needs: a cross-cultural comparison between Hong Kong Chinese and German Caucasian women with breast cancer

Androgens and musculoskeletal symptoms among breast cancer patients on aromatase inhibitor therapy

Keynote webinar | Spotlight on antibody–drug conjugates in cancer