Platelet factor 4-induced T<sub>H</sub>1-T<sub>reg</sub> polarization suppresses antitumor immunity.
basic_science · Level V
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- Record sourced from PubMed, PMID 39571033.
- Also identified by DOI 10.1126/science.adn8608.
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Abstract
The tumor microenvironment (TME) contains a number of immune-suppressive cells such as T helper 1-polarized regulatory T cells (T<sub>H</sub>1-T<sub>reg</sub> cells). However, little is known about the mechanism behind the abundant presence of T<sub>H</sub>1-T<sub>reg</sub> cells in the TME. We demonstrate that selective depletion of arginase I (Arg1)-expressing tumor-associated macrophages (Arg1<sup>+</sup> TAMs) inhibits tumor growth and concurrently reduces the ratio of T<sub>H</sub>1-T<sub>reg</sub> cells in the TME. Arg1<sup>+</sup> TAMs secrete the chemokine platelet factor 4 (PF4), which reinforces interferon-γ (IFN-γ)-induced T<sub>reg</sub> cell polarization into T<sub>H</sub>1-T<sub>reg</sub> cells in a manner dependent on CXCR3 and the IFN-γ receptor. Both genetic PF4 inactivation and PF4 neutralization hinder T<sub>H</sub>1-T<sub>reg</sub> cell accumulation in the TME and reduce tumor growth. Collectively, our study highlights the importance of Arg1<sup>+</sup> TAM-produced PF4 for high T<sub>H</sub>1-T<sub>reg</sub> cell levels in the TME to suppress antitumor immunity.
Medical subject headings
- Arginase
- Interferon-gamma
- Platelet Factor 4
- Receptors, CXCR3
- T-Lymphocytes, Regulatory
- Th1 Cells
- Tumor Microenvironment
- Tumor-Associated Macrophages
- Immune Tolerance