Engineered macrophages acting as a trigger to induce inflammation only in tumor tissues based on arginase 1-responsive TNF-α accelerated release

Kenta Tanito; Teruki Nii; Yuta Yokoyama; Haruka Oishi; Mayuka Shibata; Shoichi Hijii; Ryosuke Kaneko; Chuya Tateishi; Shoko Ito; Akihiro Kishimura; Takeshi Mori; Yoshiki Katayama

doi:10.1016/j.jconrel.2023.04.010

Engineered macrophages acting as a trigger to induce inflammation only in tumor tissues based on arginase 1-responsive TNF-α accelerated release

J Control Release. 2023 Apr 7:S0168-3659(23)00260-2. doi: 10.1016/j.jconrel.2023.04.010. Online ahead of print.

Authors

Affiliations

¹ Graduate School of Systems Life Sciences, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan.
² Graduate School of Systems Life Sciences, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan; Department of Applied Chemistry, Faculty of Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan. Electronic address: nii.teruki.204@m.kyushu-u.ac.jp.
³ Department of Applied Chemistry, Faculty of Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan.
⁴ Graduate School of Systems Life Sciences, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan; Department of Applied Chemistry, Faculty of Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan; Center for Future Chemistry, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan; International Research Center for Molecular Systems, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan.
⁵ Graduate School of Systems Life Sciences, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan; Department of Applied Chemistry, Faculty of Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan; Center for Future Chemistry, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan.
⁶ Graduate School of Systems Life Sciences, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan; Department of Applied Chemistry, Faculty of Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan; Center for Future Chemistry, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan; International Research Center for Molecular Systems, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan; Center for Advanced Medical Innovation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Department of Biomedical Engineering, Chung Yuan Christian University, 200 Chung Pei Road, Chung Li 32023, Taiwan, ROC. Electronic address: ykatatcm@mail.cstm.kyushu-u.ac.jp.

PMID: 37080488
DOI: 10.1016/j.jconrel.2023.04.010

Abstract

Herein, we report engineered macrophages, termed "MacTrigger," acting as a trigger to induce an inflammatory environment only in tumor tissues. This led to intensive anti-tumor effects based on the removal potential of foreign substances. The strength of this study is the utilization of two unique functions of macrophages: (1) their ability to migrate to tumor tissues and (2) polarization into the anti-inflammatory M2 phenotype in the presence of tumor tissues. The MacTrigger accelerated the release of inflammatory cytokines, tumor necrosis factor-alpha (TNF-α), when it was polarized to the M2 phenotype. When the MacTrigger was administered to tumor-bearing mice, tumor growth was significantly inhibited compared with the non-treatment group, the un-transfected macrophages group, and the group with engineered macrophages capable of randomly releasing TNF-α. Additionally, the ratio of the M1 phenotype to the M2 phenotype in tumor tissues was >1 only in the MacTrigger group. Moreover, the ratios of natural killer cells and CD8⁺T cells in tumor tissues were increased compared with other groups. These results indicate that MacTrigger can induce inflammation in tumor tissues, leading to effective anti-tumor effects. In normal tissues, especially the liver, notable side effects were not observed. This is because, in the liver, the MacTrigger was not polarized to the M2 phenotype and could not induce inflammation. These results suggest that the MacTrigger is a "trigger" that can induce inflammation only in tumor tissues, then allowing the body to attack tumor tissues through the innate immunity system.

Keywords: Arginase 1; Cell medicine; Inflammation induction; Macrophage; Removal potential of foreign substances; Tumor necrosis factor-α.