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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.