title: Cancer-FOXP3 directly activated CCL5 to recruit FOXP3+Treg cells in pancreatic ductal adenocarcinoma.
abstract: Forkheadbox protein 3 (FOXP3), initially identified as a key transcription factor for regulatory T cells (Treg cells), was also expressed in many tumors including pancreatic ductal adenocarcinoma (PDAC). However, its role in PDAC progression remains elusive. In this study, we utilized 120 PDAC tissues after radical resection to detect cancer-FOXP3 and Treg cells by immunohistochemistry and evaluated clinical and pathological features of these patients. Cancer-FOXP3 was positively correlated with Treg cells accumulation in tumor tissues derived from PDAC patients. In addition, high cancer-FOXP3 expression was associated with increased tumor volumes and poor prognosis in PDAC especially combined with high levels of Treg cells. Overexpression of cancer-FOXP3 promoted the tumor growth in immunocompetent syngeneic mice but not in immunocompromised or Treg cell-depleted mice. Furthermore, CCL5 was directly trans-activated by cancer-FOXP3 and promoted the recruitment of Treg cells from peripheral blood to the tumor site in vitro and in vivo. This finding has been further reinforced by the evidence that Treg cells recruitment by cancer-FOXP3 was impaired by neutralization of CCL5, thereby inhibiting the growth of PDAC. In conclusion, cancer-FOXP3 serves as a prognostic biomarker and a crucial determinant of immunosuppressive microenvironment via recruiting Treg cells by directly trans-activating CCL5. Therefore, cancer-FOXP3 could be used to select patients with better response to CCL5/CCR5 blockade immunotherapy.
authors.affiliation: Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin, China.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin, China.
authors.forename: M
authors.initials: M
authors.lastname: Lang
authors.affiliation: Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin, China.
authors.forename: T
authors.initials: T
authors.lastname: Zhao
authors.affiliation: The State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors.forename: X
authors.initials: X
authors.lastname: Feng
authors.affiliation: Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin, China.
authors.forename: C
authors.initials: C
authors.lastname: Zheng
authors.affiliation: Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin, China.
authors.forename: C
authors.initials: C
authors.lastname: Huang
authors.affiliation: Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin, China.
authors.forename: J
authors.initials: J
authors.lastname: Hao
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, Tianjin Medical University, Tianjin, China.
authors.forename: J
authors.initials: J
authors.lastname: Dong
authors.affiliation: Department of Gynaecology, Hepingqu Gynaecology and Obsterics Hospital, Tianjin, China.
authors.forename: L
authors.initials: L
authors.lastname: Luo
authors.affiliation: Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin, China.
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.affiliation: Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin, China.
authors.forename: C
authors.initials: C
authors.lastname: Lan
authors.affiliation: Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin, China.
authors.forename: W
authors.initials: W
authors.lastname: Yu
authors.affiliation: Department of Nutrition and Food Hygiene, School of Public Health, Tianjin Medical University, Tianjin, China.
authors.forename: M
authors.initials: M
authors.lastname: Yu
authors.affiliation: Penn State College of Medicine, Hershey, PA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Yang
authors.affiliation: Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin, China.
authors.forename: H
authors.initials: H
authors.lastname: Ren
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000378:metabolism / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000235:genetics; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D016513:Mice, SCID; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: D018946:Chemokine CCL5; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors