Increase in Activated Treg in TIL in Lung Cancer and In Vitro Depletion of Treg by ADCC Using an Antihuman CCR4 mAb (KM2760)

Tregs infiltrate tumors and inhibit immune responses against them. 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 sho...

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Bibliographic Details
Published in:Journal of thoracic oncology 2015-01, Vol.10 (1), p.74-83
Main Authors: Kurose, Koji, Ohue, Yoshihiro, Sato, Eiichi, Yamauchi, Akira, Eikawa, Shingo, Isobe, Midori, Nishio, Yumi, Uenaka, Akiko, Oka, Mikio, Nakayama, Eiichi
Format: Article
Language:English
Subjects:
Anti-hCCR4 mAb
Antibodies, Monoclonal - pharmacology
Antibody-Dependent Cell Cytotoxicity - drug effects
Antibody-Dependent Cell Cytotoxicity - immunology
CCR4
Cell Movement - drug effects
Cell Movement - immunology
Flow Cytometry
Forkhead Transcription Factors - immunology
Humans
In Vitro Techniques
Lung cancer
Lung Neoplasms - immunology
Lymphocyte Subsets - immunology
Lymphocytes, Tumor-Infiltrating - drug effects
Lymphocytes, Tumor-Infiltrating - immunology
Receptors, CCR4 - biosynthesis
Receptors, CCR4 - immunology
T-Lymphocytes, Regulatory - drug effects
T-Lymphocytes, Regulatory - immunology
Tissue Array Analysis
Treg depletion
Tregs
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Summary:Tregs infiltrate tumors and inhibit immune responses against them. 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. 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+ CD127dim/− 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. 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.
ISSN:1556-0864
1556-1380
DOI:10.1097/JTO.0000000000000364