Anti-CCR4 mAb selectively depletes effector-type FoxP3+CD4+ regulatory T cells, evoking antitumor immune responses in humans.
Sugiyama D, Nishikawa H, Maeda Y, Nishioka M, Tanemura A, Katayama I, Ezoe S, Kanakura Y, Sato E, Fukumori Y, Karbach J, Jäger E, Sakaguchi S.
Experimental Immunology, World Premier International Research Center, Immunology Frontier Research Center, Department of Dermatology, and Department of Hematology and Oncology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
Proc Natl Acad Sci U S A. 2013 Oct 14. [Epub ahead of print]
CD4+ Treg cells expressing the transcription factor FOXP3 (forkhead box P3) are abundant in tumor tissues and appear to hinder the induction of effective antitumor immunity. A substantial number of T cells, including Treg cells, in tumor tissues and peripheral blood express C-C chemokine receptor 4 (CCR4). Here we show that CCR4 was specifically expressed by a subset of terminally differentiated and most suppressive CD45RA-FOXP3hiCD4+ Treg cells [designated effector Treg (eTreg) cells], but not by CD45RA+FOXP3loCD4+ naive Treg cells, in peripheral blood of healthy individuals and cancer patients. In melanoma tissues, CCR4+ eTreg cells were predominant among tumor-infiltrating FOXP3+ T cells and much higher in frequency compared with those in peripheral blood. With peripheral blood lymphocytes from healthy individuals and melanoma patients, ex vivo depletion of CCR4+ T cells and subsequent in vitro stimulation of the depleted cell population with the cancer/testis antigen NY-ESO-1 efficiently induced NY-ESO-1-specific CD4+ T cells. Nondepletion failed in the induction. The magnitude of the responses was comparable with total removal of FOXP3+ Treg cells by CD25+ T-cell depletion. CCR4+ T-cell depletion also augmented in vitro induction of NY-ESO-1-specific CD8+ T cells in melanoma patients. Furthermore, in vivo administration of anti-CCR4 mAb markedly reduced the eTreg-cell fraction and augmented NY-ESO-1-specific CD8+ T-cell responses in an adult T-cell leukemia-lymphoma patient whose leukemic cells expressed NY-ESO-1. Collectively, these findings indicate that anti-CCR4 mAb treatment is instrumental for evoking and augmenting antitumor immunity in cancer patients by selectively depleting eTreg cells.
KEYWORDS: immunomodulation, cancer immunotherapy
PMID: 24127572 [PubMed - as supplied by publisher]