Abstract
It has been reported that dense intratumoral infiltration of Foxp3 +Tregs (Tregs) was an independent factor for poor prognosis of breast cancer (BC) patients. However, the cytokines activating the Treg infiltration are not known. This study was undertaken to evaluate the role of CCL22 and TGF-β1 in this cascade and their prognostic significance for BC patients. 417 cases of invasive breast cancer were selected from the prior study cohort and the expressions of CCL22 and TGF-β1 were assessed by immunohistochemistry. It was identified that tumor secretion of CCL22 was positively correlated with the intratumoral Treg infiltration (P<0.0001), but its association with lymphoid aggregates surrounding the tumor was not proven to be significant (P=0.056). Moreover, CCL22 expression was found to be associated with the tumor histological features known to be related with unfavorable prognosis of patients, including high histological grade (P<0.0001), negative ER (P<0.0001), negative PR (P=0.001), and HER2 amplification (P=0.028). Similar to intratumoral Treg infiltrates, CCL22 tumor secretion correlated with the prognosis of the molecular subtypes of breast carcinoma (P<0.0001). Univariate analysis revealed CCL22 to be an independent prognostic factor for overall survival (OS, P<0.0001) and progression-free survival (PFS, P<0.0001) of BC patients that were confirmed by multivariate analysis (P=0.011 and P=0.010 respectively). In contrast, although TGF-β1 expression was positively correlated with both Tregs infiltrates into the tumor bed and lymphoid aggregates surrounding the tumor (P=0.023; P=0.046, respectively), its expression was not significantly associated with the molecular subtypes of breast carcinoma and the prognosis of the patients. Our study indicates that both CCL22 and TGF-β1 are candidate chemoattractants for intratumoral Foxp3 +Tregs infiltration; however, unlike the later, CCL22 is an independent prognostic predictor of BC patients, and it therefore may have the potential to serve as a target for immunotherapeutic strategy of BC.
Highlights
CD4+CD25+Foxp3+regulatory T cells (Tregs) are thought to be the main obstacle tempering antitumor immunity and immunotherapy [1,2]. Their localization and the infiltrating patterns vary in breast cancer (BC) and have different impacts on tumor progression [3,4], and our prior study indicated that intratumoral Treg infiltration was an independent adverse prognostic factor for BC [5]
The present study was designed to assess the association of CCL22 and transforming growth factor-β1 (TGF-β1) expression in tumor cells with the status of Treg infiltration in invasive breast carcinoma, and in addition, to evaluate their prognostic significance for BC patients
The mechanisms through which the Tregs are recruited into the tumor microenvironment are not known in BC, in regarding which cytokines are involved in the chemotactic process, and what roles these cytokines play
Summary
CD4+CD25+Foxp3+regulatory T cells (Tregs) are thought to be the main obstacle tempering antitumor immunity and immunotherapy [1,2] Their localization and the infiltrating patterns vary in breast cancer (BC) and have different impacts on tumor progression [3,4], and our prior study indicated that intratumoral Treg infiltration was an independent adverse prognostic factor for BC [5]. Other studies have revealed that the cytokine transforming growth factor-β1 (TGF-β1) play a vital role in inducing the differentiation of Tregs [14,15] and in mediating suppression of the activation, differentiation and proliferation of immune cells [16,17] It is secreted by many types of cells, including Tregs and tumor cells. The present study was designed to assess the association of CCL22 and TGF-β1 expression in tumor cells with the status of Treg infiltration in invasive breast carcinoma, and in addition, to evaluate their prognostic significance for BC patients
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