Kuratani et al. demonstrated that VeDTR-mediated selective deletion of arginase I (Arg1)-expressing tumor-associated macrophages (Arg1+ TAMs) reduced the ratio of TH1-Treg cells in the TME, and inhibited tumor growth in subcutaneously implanted MC38 and B16F10 tumors. Arg1+ TAMs secreted the chemokine platelet factor 4 (PF4 [Cxcl4]), which polarized Tregs into TH1-Tregs in a CXCR3-dependent manner. Both genetic PF4 inactivation and mAb-mediated PF4 neutralization enhanced antitumor immunity and reduced tumor growth and the TH1-Treg ratio in the TME.
Contributed by Shishir Pant
ABSTRACT: The tumor microenvironment (TME) contains a number of immune-suppressive cells such as T helper 1-polarized regulatory T cells (T(H)1-T(reg) cells). However, little is known about the mechanism behind the abundant presence of T(H)1-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(H)1-T(reg) cells in the TME. Arg1(+) TAMs secrete the chemokine platelet factor 4 (PF4), which reinforces interferon-_ (IFN-_)-induced T(reg) cell polarization into T(H)1-T(reg) cells in a manner dependent on CXCR3 and the IFN-_ receptor. Both genetic PF4 inactivation and PF4 neutralization hinder T(H)1-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(H)1-T(reg) cell levels in the TME to suppress antitumor immunity.
Author Info: (1) Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan. Laboratory of Immunoparasitology, WPI Immunology Frontier Re
Author Info: (1) Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan. Laboratory of Immunoparasitology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan. (2) Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan. 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. Laboratory of Immunochemistry, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan. (4) Genome Information Research Center, Osaka University, Suita, Osaka, Japan. (5) Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan. Laboratory of Immunoparasitology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan. Department of Immunoparasitology, Center for Infectious Disease Education and Research, Osaka University, Suita, Osaka, Japan. Center for Advances Modalities and Drug Delivery Systems, Osaka University, Suita, Osaka, Japan. (6) Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan. (7) Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan. Laboratory of Immunochemistry, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan. Center for Advances Modalities and Drug Delivery Systems, Osaka University, Suita, Osaka, Japan. Department of Immunochemistry, Center for Infectious Disease Education and Research, Osaka University, Suita, Osaka, Japan. (8) Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan. Laboratory of Immunoparasitology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan. Department of Immunoparasitology, Center for Infectious Disease Education and Research, Osaka University, Suita, Osaka, Japan. Center for Advances Modalities and Drug Delivery Systems, Osaka University, Suita, Osaka, Japan.
