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

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.

miR141–CXCL1–CXCR2 Signaling–Induced Treg Recruitment Regulates Metastases and Survival of Non–Small Cell Lung Cancer

“…It has been proved that Tregs can be recruited to tumor microenvironment by CCL22 in ovary (22), prostate (23), gastric (9), esophageal (24), hepatocellular (25), and breast carcinomas (26)(27)(28). Qin and colleagues (10) found that CCL22 can recruit Tregs into MPE.…”

Quantification of tumor infiltrating Foxp3+ regulatory T cells enables the identification of high-risk patients for developing synchronous cancers over upper aerodigestive tract

“…Forkhead box protein 3 (Foxp3) is a key regulator for the development and function of Treg [16,17], and serves as the most specific marker to label the CD4+CD25+ Treg in human cancers [14,18]. Treg can be locally induced or selectively recruited into the tumor microenvironment mediated by IL-10, TGF-b or CCL22 [19][20][21]. The accumulation of Tregs can subsequently inhibit the host antitumor immune response, via cell-cell contact or secreting immunosuppressive cytokines, such as IL-10, IL-35 or TGF-b [15,19,22,23].…”

Higher circulating levels of chemokine CCL22 in patients with breast cancer: evaluation of the influences of tumor stage and chemokine gene polymorphism

“…Accordingly, CCL22 has important effect on suppressing immune responses to microbial infections and tumor cells by its ability to recruit Th2-and Treg cells, thereby enhancing microbial persistence and tumor development [17]. The higher expression of CCL22 has been implicated in some cancers, including colorectal adenocarcinomas [18], lung cancer [19] breast cancer [20], lymphoma [21], and head and neck squamous cell carcinoma [22].…”