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Anti-CCR4 mAb selectively depletes effector-type FoxP3⁺CD4⁺ regulatory T cells, evoking antitumor immune responses in humans

Sugiyama, Daisuke, Nishikawa, Hiroyoshi, Maeda, Yuka, Nishioka, Megumi, Tanemura, Atsushi, Katayama, Ichiro, Ezoe, Sachiko, Kanakura, Yuzuru, Sato, Eiichi, Fukumori, Yasuo, Karbach, Julia, Jäger, Elke, Sakaguchi, Shimon
Proceedings of the National Academy of Sciences of the United States of America 2013 v.110 no.44 pp. 17945-17950
CCR4 receptor, T-lymphocytes, adults, antigens, beta chemokines, humans, immune response, melanoma, patients, testes, tissues, transcription factors
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 ⁻FOXP3 ʰⁱCD4 ⁺ Treg cells [designated effector Treg (eTreg) cells], but not by CD45RA ⁺FOXP3 ˡᵒCD4 ⁺ 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.