Synergistic association of FOXP3+ tumor infiltrating lymphocytes with CCL20 expressions with poor prognosis of primary breast cancer: A retrospective cohort study

Medicine (Baltimore). 2019 Dec;98(50):e18403. doi: 10.1097/MD.0000000000018403.


Studies have shown that forkhead/winged helix transcription factor P3 (FOXP3) tumor infiltrating lymphocytes (TILs) are intimately associated with invasion and survival of many invasive tumors. The inflammatory chemokine ligand 20 (CCL20) and its receptor CCR6 were found to be associated with tumor prognosis in some studies. Although increases in FOXP3 TILs infiltration and CCL20 expression have been revealed in several malignancies, their correlation in human breast tumors is as yet unclear.Surgically resected samples from 156 patients with invasive breast cancer (BC) were assessed for the expression of FOXP3 and CCL20 by immunohistochemistry. Correlation between their expressions and the association with clinicopathological characteristics and patient's prognosis were studied. Forty pairs of fresh BC and their nontumor adjacent tissues (NATs) in BC were carried out by real-time quantitative PCR (qRT-PCR) to evaluate the correlation between FOXP3 and CCL20 mRNA expression.CCL20 and FOXP3 TILs mRNA expression in tumor tissue demonstrated a high correlation (rs = 0.359, P < .001) in this cohort of breast cancer patients. Both elevated CCL20 expression and FOXP3 TILs infiltration were significantly correlated with high histological grade, positive human epidermal growth factor receptor-2 (HER2), high Ki67 index, and axillary lymph node metastases. Tumors with concomitant high expressions of both markers had the worst prognosis. Multivariate analysis showed that these 2 markers were independent predictors of overall survival. The patients with axillary lymph node metastases with the concomitant CCL20 high expression and increased FOXP3 TILs infiltration had the worst overall survival (OS) (P < .001), In lymph node-negative breast cancer patients, the status of CCL20 and FOXP3 was not related to OS (P = .22).The results suggest that CCL20 and FOXP3 TILs may have synergistic effects, and their upregulated expressions may lead to immune evasion in breast cancer. Combinatorial immunotherapeutic approaches aiming at blocking CCL20 and depleting FOXP3 might improve therapeutic efficacy in breast cancer patients.

Publication types

  • Observational Study

MeSH terms

  • Adult
  • Biomarkers, Tumor
  • Breast Carcinoma In Situ / genetics*
  • Breast Neoplasms / genetics*
  • Carcinoma, Ductal, Breast / genetics*
  • Chemokine CCL20 / metabolism*
  • Female
  • Forkhead Transcription Factors / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Middle Aged
  • Retrospective Studies


  • Biomarkers, Tumor
  • CCL20 protein, human
  • Chemokine CCL20
  • FOXP3 protein, human
  • Forkhead Transcription Factors