Platelet factor 4-induced TH1-Treg polarization suppresses antitumor immunity

Ayumi Kuratani; Masaaki Okamoto; Kazuki Kishida; Daisuke Okuzaki; Miwa Sasai; Shimon Sakaguchi; Hisashi Arase; Masahiro Yamamoto

doi:10.1126/science.adn8608

Platelet factor 4-induced T_H1-T_reg polarization suppresses antitumor immunity

Science. 2024 Nov 22;386(6724):eadn8608. doi: 10.1126/science.adn8608. Epub 2024 Nov 22.

Authors

Ayumi Kuratani^{1

2}, Masaaki Okamoto^{1

2}, Kazuki Kishida^{3

4}, Daisuke Okuzaki⁵, Miwa Sasai^{1

2

6

7}, Shimon Sakaguchi⁸, Hisashi Arase^{3

4

7

9}, Masahiro Yamamoto^{1

2

6

7}

Affiliations

¹ Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
² Laboratory of Immunoparasitology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
³ Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
⁴ Laboratory of Immunochemistry, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
⁵ Genome Information Research Center, Osaka University, Suita, Osaka, Japan.
⁶ Department of Immunoparasitology, Center for Infectious Disease Education and Research, Osaka University, Suita, Osaka, Japan.
⁷ Center for Advances Modalities and Drug Delivery Systems, Osaka University, Suita, Osaka, Japan.
⁸ Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
⁹ Department of Immunochemistry, Center for Infectious Disease Education and Research, Osaka University, Suita, Osaka, Japan.

PMID: 39571033
DOI: 10.1126/science.adn8608

Abstract

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.

MeSH terms

Animals
Arginase* / genetics
Arginase* / metabolism
Cell Line, Tumor
Immune Tolerance*
Interferon gamma Receptor
Interferon-gamma* / immunology
Interferon-gamma* / metabolism
Mice
Mice, Inbred C57BL
Platelet Factor 4* / immunology
Receptors, CXCR3* / metabolism
T-Lymphocytes, Regulatory* / immunology
Th1 Cells* / immunology
Tumor Microenvironment* / immunology
Tumor-Associated Macrophages* / immunology
Tumor-Associated Macrophages* / metabolism

Substances

Arg1 protein, mouse
Arginase
Cxcr3 protein, mouse
Interferon gamma Receptor
Interferon-gamma
Platelet Factor 4
Receptors, CXCR3
Pf4 protein, mouse