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

Affiliations

• Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
• Laboratory of Immunoparasitology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
• Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
• Laboratory of Immunochemistry, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
• Genome Information Research Center, Osaka University, Suita, Osaka, Japan.
• Department of Immunoparasitology, Center for Infectious Disease Education and Research, Osaka University, Suita, Osaka, Japan.
• Center for Advances Modalities and Drug Delivery Systems, Osaka University, Suita, Osaka, Japan.
• Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
• Department of Immunochemistry, Center for Infectious Disease Education and Research, Osaka University, Suita, Osaka, Japan.

PMID:  39571033  DOI: 10.1126/science.adn8608

Abstract

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-γ (IFN-γ)–induced Treg cell polarization into TH1-Treg cells in a manner dependent on CXCR3 and the IFN-γ 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.

肿瘤微环境（TME）中存在大量免疫抑制细胞，其中包括T辅助1型极化的调节性T细胞（TH1-Treg细胞）。然而，导致TH1-Treg细胞在TME中大量聚集的具体机制仍不清楚。本研究发现，选择性清除表达精氨酸酶I（Arg1）的肿瘤相关巨噬细胞（Arg1+ TAMs）能够有效抑制肿瘤生长，并显著降低TME中TH1-Treg细胞的比例。进一步研究表明，Arg1+ TAMs通过分泌趋化因子血小板因子4（PF4），依赖CXCR3和干扰素-γ（IFN-γ）受体的信号通路，增强了IFN-γ诱导的Treg细胞向TH1-Treg细胞的极化能力。我们通过基因敲除和中和PF4 (anti-PF4, #6-1-5)的实验验证，PF4的功能缺失可以显著减少TH1-Treg细胞在TME中的积累，同时抑制肿瘤生长。这些结果揭示了Arg1+ TAMs分泌的PF4在TME中维持高水平TH1-Treg细胞并抑制抗肿瘤免疫中的关键作用。

关键词：PF4，Arg1，肿瘤微环境，#6-1-5，中和抗体，流式抗体，佰乐博，佰乐博生物