CCL22 Recruits CD4-positive CD25-positive Regulatory T Cells into Malignant Pleural Effusion

Abstract

Purpose: The aim of this study was to explore the presence of the chemokines CCL22 and CCL17 in malignant pleural effusion, and the chemoattractant activity of these chemokines on CD4-positive CD25-positive Foxp3-positive regulatory Tcells infiltrating into the pleural space. Experimental Design: The concentrations of CCL22 and CCL17 in both pleural effusions and sera from 33 patients with lung cancer were determined. Flow cytometry was done to determine T lymphocyte subsets in cell pellets of pleural effusion. Pleural cells were analyzed for the expression of CCL22 and CCL17. The chemoattractant activity of CCL22 for regulatory T cells in vitro and in vivo was also observed. Results: The concentration of CCL22 in malignant pleural effusion was significantly higher than that in the corresponding serum. Pleural fluid from lung cancer patients was chemotactic for regulatory T cells, and this activity was partly blocked by an anti-CCL22, but not by an anti-CCL17 antibody. Intrapleural administration of CCL22 of patients produced a marked progressive influx of regulatory T cells into pleural space. Conclusions: Compared with serum, CCL22 seemed to be increased in malignant pleural effusion, and could directly induce regulatory T cell infiltration into the pleural space in patients with malignant effusion.The development of inflammatory processes in the pleural space may result in increased pleural vascular permeability leading to the accumulation of fluid enriched in proteins, and the recruitment of cells into the pleural space (1). Although malignant pleural effusion is more and more common, very little information is available on the immune mechanisms that are involved in its development. An accumulation of lymphocytes, especially CD4-positive T lymphocytes, frequently occurs in malignant pleural effusion secondary to direct pleural involvement and/or metastases from malignancies (2, 3).Studies ongoing for more than a decade have provided firm evidence for the existence of a unique CD4-positive CD25-positive T-cell population of ''professional'' regulatory/suppressor T cells that actively and dominantly prevent both the activation and the effector function of autoreactive T cells that have escaped other mechanisms of tolerance (4 -6). CD4-positive CD25-positive Foxp3-positive regulatory T cells are believed to be involved in the control of the local immune response and in the growth of human lung cancer (7 -9). Our previous studies have shown that regulatory T cells infiltrating into human malignant pleural effusion behave as regulatory T cells (10). However, the mechanism by which regulatory T cells infiltrate into malignant pleural effusion is unknown so far. It has been reported that the chemokines CCL22 and CCL17 within the microenvironment of gastric cancer were related to the high frequency of regulatory T cells in tumorinfiltrating lymphocytes, with such an observation occurring in the early stage of gastric cancer (11). In addition, patients with malignant pleural effusion have higher percentages ...

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

“…CCL22 was associated with increased frequency of Tregs in tumor-infiltrating lymphocytes in gastric cancer (9). Interestingly, intrapleural administration of CCL22 of patients produced a marked progressive influx of Tregs into pleural space (10). These data suggest that chemokine could induce Tregs migration to the pleural space.…”

“…Qin and colleagues (10) found that CCL22 can recruit Tregs into MPE. However, their further study indicated that the recruitment of Tregs by CCL22 also exists in pleural effusion of tuberculosis (29).…”

“…MPE from patients with lung cancer or supernatant of transfected cell cultures was placed in the bottom chamber of the Transwell in a volume of 600 mL. After 4 hours of incubation at 37 C in 5% CO 2 atmosphere, cells that migrated through the filters in the lower compartment were collected, fixed, and counted by flow cytometry (10,11). To show that CXCL1 and CXCR2 were responsible for Treg migration, blocking experiments were done by mixing the MPE with 7 mg/mL of anti-CXCL1 or mixing the Tregs with 2 mg/mL of anti-CXCR2 (R&D Systems Inc.).…”

Characterization of T cell repertoire of blood, tumor, and ascites in ovarian cancer patients using next generation sequencing

“…This difference might be caused by the levels of some cytokines in tumor tissues and malignant fluids. Although many studies have characterized the changes of immune microenvironment through recruitment of leukocytes induced by chemokines, [35][36][37][38][39] it could be also important to elucidate the relation between expansion of T cell clonotypes and expression of chemokines.…”

Characterizing the interaction of CCL17 with CCR4: Elucidating requirements to elicit cellular function

“…CCL22 function is the effect on Treg homeostasis in that CCL17, but not CCL22 had been shown to modulate Treg function through its effect on dendritic cells, while CCL22 has been shown to play a more dominant role in Treg recruitment [10][11][12][13] . In contrast, mouse models of invasive Aspergillosis have revealed that CCL17 suppresses the anti-fungal response whereas CCL22 is involved in mediating fungal clearance [14] .…”