Platelet factor 4-induced TH1-Treg polarization suppresses antitumor immunity

• 成果类型: Article
• 署名作者: Kuratani, Ayumi; Okamoto, Masaaki; Kishida, Kazuki; Okuzaki, Daisuke; Sasai, Miwa; Sakaguchi, Shimon; Arase, Hisashi; Yamamoto, Masahiro
• 署名单位: University of Osaka; University of Osaka; University of Osaka; University of Osaka; University of Osaka; University of Osaka; University of Osaka; University of Osaka; University of Osaka
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9559
• DOI: 10.1126/science.adn8608
• 发表日期: 2024-11-22
• 关键词: regulatory t-cells; tumor-associated macrophages; factor-iv; cxc chemokines; inhibition; expression; GROWTH; progression; carcinoma; reveals

摘要

The tumor microenvironment (TME) contains a number of immune-suppressive cells such as T helper 1-polarized regulatory T cells (TH1-Treg cells). However, little is known about the mechanism behind the abundant presence of TH1-Treg cells in the TME. We demonstrate that selective depletion of arginase I (Arg1)-expressing tumor-associated macrophages (Arg1+ TAMs) inhibits tumor growth and concurrently reduces the ratio of TH1-Treg cells in the TME. Arg1+ TAMs secrete the chemokine platelet factor 4 (PF4), which reinforces interferon-gamma (IFN-gamma)-induced Treg cell polarization into TH1-Treg cells in a manner dependent on CXCR3 and the IFN-gamma receptor. Both genetic PF4 inactivation and PF4 neutralization hinder TH1-Treg cell accumulation in the TME and reduce tumor growth. Collectively, our study highlights the importance of Arg1+ TAM-produced PF4 for high TH1-Treg cell levels in the TME to suppress antitumor immunity.