title: Increase in activated Treg in TIL in lung cancer and in vitro depletion of Treg by ADCC using an antihuman CCR4 mAb (KM2760).
abstract: BACKGROUND
  Tregs infiltrate tumors and inhibit immune responses against them.
  
  
  METHODS
  We investigated subpopulations of Foxp3 CD4 T cells previously defined by Miyara et al. (Immunity 30, 899-911, 2009) in peripheral blood mononuclear cells (PBMCs) and tumor infiltrating lymphocytes (TILs) in lung cancer. We also showed that Tregs in healthy donors that express CCR4 could be efficiently eliminated in vitro by cotreatment with antihuman (h) CCR4 mAb (KM2760) and NK cells.
  
  
  RESULTS
  In lung cancer, the number of activated/effector Tregs and non-Tregs, but not resting/naive Tregs, was increased in TILs compared with the number of those cells in PBMCs. The non-Treg population contained Th2 and Th17. CCR4 expression on activated/effector Tregs and non-Tregs in TILs was down-regulated compared with that on those cells in PBMCs. Chemokinetic migration of CD25 CD4 T cells containing the Treg population sorted from the PBMCs of healthy donors to CCL22/MDC was abrogated by pretreatment with anti-hCCR4 mAb (KM2760). The inhibitory activity of CD25 CD127 CD4 Tregs on the proliferative response of CD4 and CD8 T cells stimulated with anti-CD3/CD28 coated beads was abrogated by adding an anti-hCCR4 mAb (KM2760) and CD56 NK cells to the culture.
  
  
  CONCLUSIONS
  The findings suggested the CCR4 on activated/effector Tregs and non-Tregs was functionally involved in the chemokinetic migration and accumulation of those cells to the tumor site. In vitro findings of efficient elimination of Tregs may give the basis for implementation of a clinical trial to investigate Treg depletion by administration of an anti-hCCR4 mAb to solid cancer patients.
authors.affiliation: *Department of Respiratory Medicine, Kawasaki Medical School, Kurashiki, Japan; †Department of Pathology, Tokyo Medical University, Tokyo, Japan; ‡Department of Biochemistry, Kawasaki Medical School, Kurashiki, Japan; §Department of Immunology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; and ‖Faculty of Health and Welfare, Kawasaki University of Medical Welfare, Kurashiki, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Kurose
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ohue
authors.forename: Eiichi
authors.initials: E
authors.lastname: Sato
authors.forename: Akira
authors.initials: A
authors.lastname: Yamauchi
authors.forename: Shingo
authors.initials: S
authors.lastname: Eikawa
authors.forename: Midori
authors.initials: M
authors.lastname: Isobe
authors.forename: Yumi
authors.initials: Y
authors.lastname: Nishio
authors.forename: Akiko
authors.initials: A
authors.lastname: Uenaka
authors.forename: Mikio
authors.initials: M
authors.lastname: Oka
authors.forename: Eiichi
authors.initials: E
authors.lastname: Nakayama
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology; D006801:Humans; D066298:In Vitro Techniques; D008175:Lung Neoplasms / Q000276:immunology*; D016131:Lymphocyte Subsets / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology*; D054398:Receptors, CCR4 / Q000096:biosynthesis / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D046888:Tissue Array Analysis
chemical_list: D000911:Antibodies, Monoclonal; C515354:CCR4 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D054398:Receptors, CCR4