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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.

Tumor Secretion of CCL22 Activates Intratumoral Treg Infiltration and Is Independent Prognostic Predictor of Breast Cancer