Abstract A078: Platelet factor 4 (PF4)-dependent suppression of anti-tumor immunity by Th1-Treg polarization can be a novel immunotherapeutic target

Abstract The tumor microenvironment (TME) contains a number of immune-suppressive cells such as T helper 1-polarized regulatory T cells (Th1-Tregs) that strongly inhibit anti-tumor immunity. However, little is known about the mechanism behind the abundant presence of Th1-Tregs in the TME. Here we have created a mouse line, in which tumor associated macrophages (TAMs) can be selectively depleted using VeDTR mouse system. Suprisingly, we found that selective depletion of arginase I-expressing TAMs (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 polarization into Th1-Tregs. Both genetic PF4 inactivation and PF4 neutralization hinder Th1-Treg accumulation in the TME and reduce tumor growth. Collectively, our study highlights the importance of Arg1+ TAM-produced PF4 for high Th1-Treg levels in the TME to suppress anti-tumor immunity, and demonstrates that its intervension can be a novel oncoimmunotherapeutic measure. Citation Format: Masahiro Yamamoto, Ayumi Kuratani. Platelet factor 4 (PF4)-dependent suppression of anti-tumor immunity by Th1-Treg polarization can be a novel immunotherapeutic target [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A078.