Blockade of PF4-induced Th1-Treg polarization enhances anti-tumor immunity (Bulk RNA-Seq)

The tumor microenvironment (TME) contains various immune-suppressive cells such as T helper 1-polarized regulatory T cells (Th1-Tregs). However, little is known about the mechanism behind the abundant presence of Th1-Tregs in TME. In this work, we demonstrate that selective depletion of arginase I (Arg1)-expressing tumor associated macrophages (Arg1+ TAMs) inhibits tumor growth and concurrently reduces the Th1-Treg ratio in TME. Notably, Arg1+ TAMs secrete platelet factor 4 (PF4) that reinforces interferon-? (IFN-?)-induced Treg polarization into Th1-Tregs in a manner dependent on CXCR3 and the IFN-? receptor. Both genetic PF4 inactivation and PF4 neutralization hinder Th1-Treg accumulation in TME, consequently suppressing tumor growth. Collectively, our study highlights the importance of Arg1+ TAM-produced PF4 for high Th1-Treg levels in TME to suppress anti-tumor immunity, and demonstrates PF4 neutralization as a potential cancer immunotherapeutic strategy. Overall design: Bulk RNA-seq analysis of gene expression profiles in intra-tumoral RFP(+) or RFP(-) CD45+, Ly6C(-), Ly6G(-), NK1.1(-), B220(-), CD90.2(-), MHCII(+), F4/80(+), CD11b(+) cells (TAMs) from B16F10- or MC38-bearing Arg1-RFP mice (n = 3).