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
BMC Cancer
Published in: BMC Cancer 1/2018

Open Access 01-12-2018 | Research article

CCL1 is a major regulatory T cell attracting factor in human breast cancer

Authors: Benjamin Kuehnemuth, Ignazio Piseddu, Gabriela M. Wiedemann, Michael Lauseker, Christina Kuhn, Simone Hofmann, Elisa Schmoeckel, Stefan Endres, Doris Mayr, Udo Jeschke, David Anz

Published in: BMC Cancer | Issue 1/2018

Login to get access

Abstract

Background

Regulatory T cells (Treg) suppress cytotoxic T cell anti-tumoral immune responses and thereby promote tumor progression. Prevention of intratumoral Treg accumulation by inhibition of their migration to the tumor microenvironment is a promising therapeutic strategy. The aim of this study was to identify the role of the two major Treg-attracting chemokines CCL1 and CCL22 in human breast cancer.

Methods

One hundred ninety-nine tissue samples of patients with invasive breast cancer were stained for CCL1 and CCL22 by immunohistochemistry. Chemokine expression and tumor infiltration by regulatory T cells, determined by expression of the transcription factor FoxP3, were quantified and their correlation to clinical features was statistically analyzed.

Results

Both CCL1 and CCL22 were expressed in most breast cancer tissues. CCL1 was significantly over-expressed in invasive breast cancer as compared to normal breast tissue. CCL1, but surprisingly not CCL22, showed a significant correlation with the number of tumor-infiltrating FoxP3+ Treg (p< 0.001). High numbers of intratumoral CCL1 expressing cells were related to high grade tumors (G4) and a positive estrogen receptor (ER) status whereas high CCL22 expression was generally seen in lower grade tumors. The median survival of 88 patients with high intratumoral CCL1 expression was 37 months compared to 50 months for the 87 patients with low CCL1 levels, this trend was however not statistically significant.

Conclusions

We found a high expression of CCL1 in human breast cancer. CCL1 significantly correlated with the infiltration of immunosuppressive FoxP3+ Treg, that are known to negatively affect survival. Thus, CCL1 may serve as prognostic marker and novel therapeutic target in breast cancer.
Literature
1.
2.
Chen L, et al. Trends in 5-year survival rates among breast cancer patients by hormone receptor status and stage. Breast Cancer Res Treat. 2014;147(3):609–16.PubMedPubMedCentralCrossRef
3.
4.
5.
Nanda R, et al. Pembrolizumab in patients with advanced triple-negative breast Cancer: phase Ib KEYNOTE-012 study. J Clin Oncol. 2016;34(21):2460–7.PubMedCrossRef
6.
Polk A, et al. Checkpoint inhibitors in breast cancer - current status. Cancer Treat Rev. 2017;63:122–34.PubMedCrossRef
7.
Rugo HS, et al. Abstract S5-07: preliminary efficacy and safety of pembrolizumab (MK-3475) in patients with PD-L1–positive, estrogen receptor-positive (ER+)/HER2-negative advanced breast cancer enrolled in KEYNOTE-028. Cancer Res. 2016;76(4 Supplement):S5–07.
8.
Sylvia A, et al. Phase Ib trial of atezolizumab in combination with nab-paclitaxel in patients with metastatic triple-negative breast cancer (mTNBC). J Clin Oncol. 2016;34(15_suppl):1009.CrossRef
9.
Sakaguchi S. Regulatory T cells: key controllers of immunologic self-tolerance. Cell. 2000;101(5):455–8.PubMedCrossRef
10.
Lim HW, et al. Cutting edge: direct suppression of B cells by CD4+ CD25+ regulatory T cells. J Immunol. 2005;175(7):4180–3.PubMedCrossRef
11.
Trzonkowski P, et al. CD4+CD25+ T regulatory cells inhibit cytotoxic activity of T CD8+ and NK lymphocytes in the direct cell-to-cell interaction. Clin Immunol. 2004;112(3):258–67.PubMedCrossRef
12.
Betts GJ, et al. Regulating the immune response to tumours. Adv Drug Deliv Rev. 2006;58(8):948–61.PubMedCrossRef
13.
Fu J, et al. Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology. 2007;132(7):2328–39.PubMedCrossRef
14.
Sasada T, et al. CD4+CD25+ regulatory T cells in patients with gastrointestinal malignancies: possible involvement of regulatory T cells in disease progression. Cancer. 2003;98(5):1089–99.PubMedCrossRef
15.
Denkert C, et al. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol. 2010;28(1):105–13.CrossRef
16.
Issa-Nummer Y, 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(12):e79775.PubMedPubMedCentralCrossRef
17.
Mahmoud SM, et al. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin Oncol. 2011;29(15):1949–55.PubMedCrossRef
18.
Bense RD, et al. Relevance of Tumor-Infiltrating Immune Cell Composition and Functionality for Disease Outcome in Breast Cancer. J Natl Cancer Inst. 2017;109:1.CrossRef
19.
Shou J, et al. Worse outcome in breast cancer with higher tumor-infiltrating FOXP3+ Tregs : a systematic review and meta-analysis. BMC Cancer. 2016;16:687.PubMedPubMedCentralCrossRef
20.
Wang Y, et al. Regulatory T cells are an important prognostic factor in breast cancer: a systematic review and meta-analysis. Neoplasma. 2016;63(5):789–98.PubMedCrossRef
21.
Curiel TJ, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004;10(9):942–9.PubMedCrossRef
22.
Maruyama T, et al. CCL17 and CCL22 chemokines within tumor microenvironment are related to infiltration of regulatory T cells in esophageal squamous cell carcinoma. Dis Esophagus. 2010;23(5):422–9.PubMed
23.
Mizukami Y, et al. CCL17 and CCL22 chemokines within tumor microenvironment are related to accumulation of Foxp3+ regulatory T cells in gastric cancer. Int J Cancer. 2008;122(10):2286–93.PubMedCrossRef
24.
Wagsater D, et al. Quantification of the chemokines CCL17 and CCL22 in human colorectal adenocarcinomas. Mol Med Rep. 2008;1(2):211–7.PubMed
25.
Gobert M, et al. 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. 2009;69(5):2000–9.
26.
27.
Xu Y, et al. Sox2 communicates with Tregs through CCL1 to promote the Stemness property of breast. Cancer Cells. 2017;35(12):2351–65.
28.
Freier, CP. Role of regulatory T cells and associated chemokines in human gynecological tumors. Dissertation, LMU München: Medizinische Fakultät. Munich, 2016.
29.
Freier CP, et al. FOXP3+ cells recruited by CCL22 into breast Cancer correlates with less tumor nodal infiltration. Anticancer Res. 2016;36(6):3139–45.PubMed
30.
Bates GJ, et al. Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol. 2006;24(34):5373–80.PubMedCrossRef
31.
Anz D, et al. In breast cancer, a high ratio of tumour-infiltrating intraepithelial CD8+ to FoxP3+ cells is characteristic for the medullary subtype. Histopathology. 2011;59(5):965–74.PubMedCrossRef
32.
Hoelzinger DB, et al. Blockade of CCL1 inhibits T regulatory cell suppressive function enhancing tumor immunity without affecting T effector responses. J Immunol. 2010;184(12):6833–42.PubMedCrossRef
33.
Shang B, et al. Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: a systematic review and meta-analysis. Sci Rep. 2015;5:15179.PubMedPubMedCentralCrossRef
34.
Ghia P, et al. Chronic lymphocytic leukemia B cells are endowed with the capacity to attract CD4+, CD40L+ T cells by producing CCL22. Eur J Immunol. 2002;32(5):1403–13.PubMedCrossRef
35.
Yang P, et al. TGF-beta-miR-34a-CCL22 signaling-induced Treg cell recruitment promotes venous metastases of HBV-positive hepatocellular carcinoma. Cancer Cell. 2012;22(3):291–303.PubMedPubMedCentralCrossRef
36.
Facciabene A, et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T (reg) cells. Nature. 2011;475(7355):226–30.PubMedCrossRef
37.
Tan MC, et al. Disruption of CCR5-dependent homing of regulatory T cells inhibits tumor growth in a murine model of pancreatic cancer. J Immunol. 2009;182(3):1746–55.PubMedPubMedCentralCrossRef
38.
Chen KJ, et al. Selective recruitment of regulatory T cell through CCR6-CCL20 in hepatocellular carcinoma fosters tumor progression and predicts poor prognosis. PLoS One. 2011;6(9):e24671.PubMedPubMedCentralCrossRef
39.
40.
Palacios-Arreola MI, et al. The role of chemokines in breast cancer pathology and its possible use as therapeutic targets. J Immunol Res. 2014;2014:849720.PubMedPubMedCentralCrossRef
41.
Ben-Baruch A. The multifaceted roles of chemokines in malignancy. Cancer Metastasis Rev. 2006;25(3):357–71.PubMedCrossRef
42.
Fujimoto H, et al. Stromal MCP-1 in mammary tumors induces tumor-associated macrophage infiltration and contributes to tumor progression. Int J Cancer. 2009;125(6):1276–84.PubMedCrossRef
43.
Soria G, Ben-Baruch A. The inflammatory chemokines CCL2 and CCL5 in breast cancer. Cancer Lett. 2008;267(2):271–85.PubMedCrossRef
44.
Ueno T, et al. Significance of macrophage chemoattractant protein-1 in macrophage recruitment, angiogenesis, and survival in human breast cancer. Clin Cancer Res. 2000;6(8):3282–9.PubMed
45.
Faget J, et al. Early detection of tumor cells by innate immune cells leads to T (reg) recruitment through CCL22 production by tumor cells. Cancer Res. 2011;71(19):6143–52.PubMedCrossRef
46.
Metadata
Title
CCL1 is a major regulatory T cell attracting factor in human breast cancer
Authors
Benjamin Kuehnemuth
Ignazio Piseddu
Gabriela M. Wiedemann
Michael Lauseker
Christina Kuhn
Simone Hofmann
Elisa Schmoeckel
Stefan Endres
Doris Mayr
Udo Jeschke
David Anz
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-018-5117-8

Other articles of this Issue 1/2018

BMC Cancer 1/2018 Go to the issue

Research article

Comparison of Germline versus Somatic BAP1 Mutations for Risk of Metastasis in Uveal Melanoma

Research article

Sleep duration and the risk of cancer: a systematic review and meta-analysis including dose–response relationship

Research article

Prognostic value of the fibrinogen/albumin ratio (FAR) in patients with operable soft tissue sarcoma

Research article

Comparison of the seventh and eighth editions of the UICC/AJCC staging system for nasopharyngeal carcinoma: analysis of 1317 patients treated with intensity-modulated radiotherapy at two centers

Research article

Glucose, lipids and gamma-glutamyl transferase measured before prostate cancer diagnosis and secondly diagnosed primary tumours: a prospective study in the Swedish AMORIS cohort

Research article

Aberrant Promoter Methylation of YAP Gene and its Subsequent Downregulation in Indian Breast Cancer Patients
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