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.
Science. 2024 Nov 22;386(6724):eadn8608. doi: 10.1126/science.adn8608.
The tumor microenvironment (TME) contains a number of immune-suppressive cells such as T helper 1-polarized regulatory T cells (T1-T cells). However, little is known about the mechanism behind the abundant presence of T1-T 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 T1-T cells in the TME. Arg1 TAMs secrete the chemokine platelet factor 4 (PF4), which reinforces interferon-γ (IFN-γ)-induced T cell polarization into T1-T cells in a manner dependent on CXCR3 and the IFN-γ receptor. Both genetic PF4 inactivation and PF4 neutralization hinder T1-T cell accumulation in the TME and reduce tumor growth. Collectively, our study highlights the importance of Arg1 TAM-produced PF4 for high T1-T cell levels in the TME to suppress antitumor immunity.
肿瘤微环境（TME）包含许多免疫抑制性细胞，如 T 辅助 1 极化的调节性 T 细胞（T1-T 细胞）。然而，TME 中大量存在 T1-T 细胞的背后机制尚不清楚。我们证明，选择性耗尽表达精氨酸酶 I（Arg1）的肿瘤相关巨噬细胞（Arg1 TAMs）可抑制肿瘤生长，并同时降低 TME 中 T1-T 细胞的比例。Arg1 TAMs 分泌趋化因子血小板因子 4（PF4），以依赖于 CXCR3 和 IFN-γ 受体的方式增强干扰素-γ（IFN-γ）诱导的 T 细胞向 T1-T 细胞的极化。PF4 的基因失活和中和均阻碍了 TME 中 T1-T 细胞的积累，并降低了肿瘤生长。总之，我们的研究强调了 Arg1 TAM 产生的 PF4 对于 TME 中高水平 T1-T 细胞抑制抗肿瘤免疫的重要性。
