CCL17 and CCL22 chemokines within tumor microenvironment are related to infiltration of regulatory T cells in esophageal squamous cell carcinoma

Abstract

It has been reported that an increased population of regulatory T cells (T-regs) is one of the reasons for impaired anti-tumor immunity. We investigated the frequency of Foxp3(+) T-regs in tumor-infiltrating lymphocytes (TILs) and peripheral blood lymphocytes (PBLs) of patients with esophageal squamous cell carcinoma (ESCC). Furthermore, in order to elucidate the mechanisms behind T-regs accumulation within tumors, we evaluated the relationship between CCL17 or CCL22 expression and the frequency of Foxp3(+) T-regs. CD4(+)CD25(+)Foxp3(+) T-regs as a percentage of CD4(+) cells were counted by flow cytometry. The frequency of CCL17(+) or CCL22(+) cells among CD14(+) cells in tumors was also evaluated by flow cytometry. Moreover, an in vitro migration assay using T-regs derived from ESCC was performed in the presence of CCL17 or CCL22. The frequency of Foxp3(+) T-regs in TILs was significantly higher than that in the normal esophageal mucosa (24.6 +/- 10.0 vs 7.1 +/- 5.9%, P < 0.01). The frequency of Foxp3(+) T-regs in PBLs of ESCC patients was significantly higher than that in normal healthy donors (7.0 +/- 4.2 vs 2.5 +/- 1.0%, P < 0.01). Furthermore, the frequency of CCL17(+) or CCL22(+) cells among CD14(+) cells within tumors was significantly higher than that of normal esophageal mucosa, and there was a significant correlation between the frequency of CCL17(+) or CCL22(+) cells and Foxp3(+) T-regs in TILs. In addition, the in vitro migration assay indicated that T-regs were significantly induced to migrate by CCL17 or CCL22. In conclusion, CCL17 and CCL22 within the tumor are related to the increased population of Foxp3(+) T-regs in ESCC.

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

“…These results suggest that the elevated levels of chemokine CCL22 may contribute in the progression of breast cancer. A number of studies have indicated that CCL22 secretion by tumor cells is responsible for intratumoral accumulation of Tregs in ovarian cancer [41], prostate cancer [42], gastric cancer [43], esophageal carcinoma [44], and breast carcinoma [45]. However, it may be concluded that the CCL22 production by tumors cells and/or tumorinfiltrating macrophages induces the intratumoral accumulation of Tregs.…”

Suppression, subversion and escape: the role of regulatory T cells in cancer progression

“…Blockade of CCL22 reduced Treg infiltration into ovarian tumours and induced tumour rejection in a murine xenograft model [30]. CCR4 also appears to facilitate Treg tumour infiltration in gastric cancer [35] and oesophageal squamous cell carcinoma [36]. Another chemokine, CCL28, can be expressed by tumour cells during hypoxia, and it is reported to recruit preferentially Tregs expressing CCR10 [37], while in a murine model of pancreatic cancer Tregs have been shown to be recruited to the tumour site via a CCL5/CCR5 axis [38].…”

An imbalance between innate and adaptive immune cells at the maternal–fetal interface occurs prior to endotoxin-induced preterm birth

“…56,57 Endotoxin administration to pregnant mice did not reduce the production of CCL17 or CCL22; instead, it increased the concentration of these chemokines in the uterine tissues. These data demonstrate that the reduced number of uterine CD41Tregs is not associated with low concentrations of CCL17 and CCL22 in the uterine tissues.…”

“…48,49 CCL17 and CCL22 participate in the recruitment of Tregs into the site of inflammation. 56,57 Therefore, we investigated whether the reduction of CD41 Tregs caused by endotoxin administration was due to a diminished production of CCL17 and CCL22 by the uterine tissues. Chemokine concentrations were quantified by ELISAs in uterine protein extracts from pregnant mice injected with PBS or LPS.…”