期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 116, 期 2, 页码 609-618出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1812186116
关键词
regulatory T cells; CTLA-4; FOXP3; cancer immunotherapy; antibody-dependent cell-mediated cytotoxicity
资金
- Ministry of Education, Culture, Sports, Science and Technology of Japan [16H06295, 26253030, 26290054, 26670581, 26860331, 17K15723]
- Core Research for Evolutional Science and Technology from Japan Science and Technology Agency
- Grants-in-Aid for Scientific Research [17K15723, 26670581, 26253030, 26290054, 26860331, 16H06295] Funding Source: KAKEN
Anti-CTLA-4 mAb is efficacious in enhancing tumor immunity in humans. CTLA-4 is expressed by conventional T cells upon activation and by naturally occurring FOXP3(+)CD4(+) Treg cells constitutively, raising a question of how anti-CTLA-4 mAb can differentially control these functionally opposing T cell populations in tumor immunity. Here we show that FOXP3(high) potently suppressive effector Treg cells were abundant in melanoma tissues, expressing CTLA-4 at higher levels than tumor-infiltrating CD8(+)T cells. Upon in vitro tumor-antigen stimulation of peripheral blood mononuclear cells from healthy individuals or melanoma patients, Fc-region-modified anti-CTLA-4 mAb with high antibody-dependent cell-mediated cytotoxicity (ADCC) and cellular phagocytosis (ADCP) activity selectively depleted CTLA-4(+)FOXP3(+) Treg cells and consequently expanded tumor-antigen-specific CD8(+)T cells. Importantly, the expansion occurred only when antigen stimulation was delayed several days from the antibody treatment to spare CTLA-4(+) activated effector CD8(+)T cells from mAb-mediated killing. Similarly, in tumor-bearing mice, high-ADCC/ADCP anti-CTLA-4 mAb treatment with delayed tumor-antigen vaccination significantly prolonged their survival and markedly elevated cytokine production by tumor-infiltrating CD8(+)T cells, whereas antibody treatment concurrent with vaccination did not. Anti-CTLA4 mAb modified to exhibit a lesser or no Fc-binding activity failed to show such timing-dependent in vitro and in vivo immune enhancement. Thus, high ADCC anti-CTLA-4 mAb is able to selectively deplete effector Treg cells and evoke tumor immunity depending on the CTLA-4-expressing status of effector CD8(+)T cells. These findings are instrumental in designing cancer immunotherapy with mAbs targeting the molecules commonly expressed by FOXP3(+) Treg cells and tumor-reactive effector T cells.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据