Platelet factor 4–induced T H 1-T reg polarization suppresses antitumor immunity

The tumor microenvironment (TME) contains a number of immune-suppressive cells such as T helper 1–polarized regulatory T cells (T H 1-T reg cells). However, little is known about the mechanism behind the abundant presence of T H 1-T reg 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 T H 1-T reg cells in the TME. Arg1 + TAMs secrete the chemokine platelet factor 4 (PF4), which reinforces interferon-γ (IFN-γ)–induced T reg cell polarization into T H 1-T reg cells in a manner dependent on CXCR3 and the IFN-γ receptor. Both genetic PF4 inactivation and PF4 neutralization hinder T H 1-T reg cell accumulation in the TME and reduce tumor growth. Collectively, our study highlights the importance of Arg1 + TAM–produced PF4 for high T H 1-T reg cell levels in the TME to suppress antitumor immunity.