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

Xia Zhao,Yanhua Yuan,Xiaoli Wang,Jun Ren,Shuzhen Lv,Yanping Li,Jiangping Wu

doi:10.1097/md.0000000000018403

Abstract

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.

Highlights

According to statistics from the International Agency for Research on Cancer GLOBOCAN database, the global incidence of breast cancer is ranked first among cancers in women
The results suggest that corresponding receptors.[25] Chemokine ligand 20 (CCL20) and FOXP3+ tumor infiltrating lymphocytes (TILs) may have synergistic effects, and their upregulated expressions may lead to immune evasion in breast cancer
High CCL20 expression and increased FOXP3+ TILs infiltrates were both associated with high histological grade, axillary lymph node metastases, positive human epidermal growth factor receptor-2 (HER2), and high Ki67 index but not correlated with age, tumor size, estrogen receptor (ER) status

Summary

Introduction

According to statistics from the International Agency for Research on Cancer GLOBOCAN database, the global incidence of breast cancer is ranked first among cancers in women. In 2015, the United States had approximately 231,840 new cases of invasive breast cancer and 40,290 cases of breast cancer-related deaths.[1] In China, breast cancer shows an overall increasing trend in the last few decades, an annual increase of 3% to 5% and a 5-year overall survival rate of 72.7%.[2] Relapse and metastasis are the primary causes of death in breast cancer patients. 30% to 40% of breast cancer patients will progress to metastatic disease, with a median survival of 3 years.[2]. Effective immune evasion by cancer cells is a crucial step during cancer occurrence, progression, and metastasis. As functional immunosuppressive T-cells, regulatory T-cells (Tregs) play important roles in immune tolerance and immune evasion.[3,4] Currently, the inhibitory mechanisms of Tregs are still unclear. More and more evidence has shown that increased numbers of

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