Platelet factor 4-induced T_H1-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_H1-T_reg cells). However, little is known about the mechanism behind the abundant presence of T_H1-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_H1-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_H1-T_reg cells in a manner dependent on CXCR3 and the IFN-γ receptor. Both genetic PF4 inactivation and PF4 neutralization hinder T_H1-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_H1-T_reg cell levels in the TME to suppress antitumor immunity.