Tanito Kenta, Nii Teruki, Yokoyama Yuta, Oishi Haruka, Shibata Mayuka, Hijii Shoichi, Kaneko Ryosuke, Tateishi Chuya, Ito Shoko, Kishimura Akihiro, Mori Takeshi, Katayama Yoshiki
Graduate School of Systems Life Sciences, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan.
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.
J Control Release. 2023 Apr 12. doi: 10.1016/j.jconrel.2023.04.010.
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 CD8T 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.
在此，我们报告了一种经过工程改造的巨噬细胞，称为“MacTrigger”，它可作为一种触发因素，仅在肿瘤组织中诱导炎症环境。基于对外源物质的清除潜力，这导致了强烈的抗肿瘤作用。本研究的优势在于利用了巨噬细胞的两种独特功能：（1）它们迁移至肿瘤组织的能力；（2）在肿瘤组织存在的情况下极化为抗炎M2表型的能力。当MacTrigger极化为M2表型时，它加速了炎性细胞因子肿瘤坏死因子-α（TNF-α）的释放。当将MacTrigger给予荷瘤小鼠时，与未治疗组、未转染巨噬细胞组以及能够随机释放TNF-α的工程巨噬细胞组相比，肿瘤生长受到显著抑制。此外，仅在MacTrigger组中，肿瘤组织中M1表型与M2表型的比例>1。而且，与其他组相比，肿瘤组织中自然杀伤细胞和CD8T细胞的比例增加。这些结果表明，MacTrigger可在肿瘤组织中诱导炎症，从而导致有效的抗肿瘤作用。在正常组织中，尤其是肝脏，未观察到明显的副作用。这是因为在肝脏中，MacTrigger未极化为M2表型，无法诱导炎症。这些结果表明，MacTrigger是一种“触发因素”，它仅能在肿瘤组织中诱导炎症，进而使机体通过先天免疫系统攻击肿瘤组织。
