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

ABSTRACT: 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-γ (IFN-γ)-induced Treg polarization into Th1-Tregs in a manner dependent on CXCR3 and the IFN-γ 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE252052 | GEO | 2024/11/07

REPOSITORIES: GEO

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Blockade of PF4-induced Th1-Treg polarization enhances anti-tumor immunity

Project description:The tumor microenvironment (TME) contains various immune-suppressive cells such as regulatory T cells (Tregs) and M2-like tumor associated macrophages (TAMs) that express the enzyme arginase I (Arg1). T helper 1-polarized Treg (Th1-Treg) is a Treg subset that markedly accumulate in tumor tissues, suppressing anti-tumor immunity. However, little is known about the mechanism behind the abundant presence of Th1-Tregs in TME. Here we show that Arg1-expressing TAMs (Arg1+ TAMs) play critical roles for the high Th1-Treg ratio in TME. Selective depletion of Arg1+ TAMs using the VeDTR system inhibited tumor growth and concurrently reduced the Th1-Treg ratio in TME. Notably, Arg1+ TAMs secreted platelet factor 4 (PF4) that polarized Tregs to Th1-Tregs in a CXCR3-dependent manner. Both genetic PF4 inactivation and PF4 neutralization hindered Th1-Treg accumulation in TME, consequently suppressing tumor growth. Collectively, our study highlights the importance of M2-like 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 by intervening the M2-like TAM/Th1-Treg axis.

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