肿瘤微环境诱导工程巨噬细胞分泌 TRAIL,用于抗肿瘤治疗

IF 3.7 4区 医学 Q2 CELL BIOLOGY
Qinyao Zhu , Xin Huang , Botian Deng , Lili Guan , Hui Zhou , Binhe Shi , Junhua Liu , Xiaojiao Shan , Xiaobin Fang , Fengtao Xu , Huan Li , Xiyang Liu , Xiushan Yin , Luo Zhang
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引用次数: 0

摘要

巨噬细胞具有高度可塑性和长期持久性,是传递抗肿瘤细胞因子的绝佳载体。巨噬细胞传递趋化因子和细胞因子在肿瘤治疗中显示出潜力。TRAIL是一种很有前景的抗肿瘤细胞因子,它能诱导肿瘤细胞凋亡,对正常细胞毒性较低。然而,它的脱靶毒性和有限的稳定性限制了其临床应用的进展。在这里,我们用 Mono-TRAIL 和 Tri-TRAIL 改造了巨噬细胞,发现 Tri-TRAIL 在体外对肿瘤细胞的细胞毒活性高于 Mono-TRAIL。为了针对肿瘤微环境(TME),我们生成了由肿瘤微环境特异性启动子 Arg1 诱导分泌三聚 TRAIL(Tri-TRAIL-iM)的巨噬细胞。Tri-TRAIL-iM 细胞在基于细胞的共培养试验和肿瘤小鼠模型中显示出很高的特异性激活活性。此外,我们还证明,与在非诱导启动子下过度表达 TRAIL 的巨噬细胞相比,Tri-TRAIL-iM 能更有效地诱导癌细胞凋亡、抑制肿瘤生长并减少全身副作用。这种诱导 TRAIL 递送的策略在癌症治疗中具有巨大潜力。它有望与其他工程方法相结合,最大限度地提高实体瘤的治疗效果。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Tumor micro-environment induced TRAIL secretion from engineered macrophages for anti-tumor therapy

The high plasticity and long-term persistency make macrophages excellent vehicles for delivering anti-tumor cytokines. Macrophage delivery of chemokines and cytokines shows potential in tumor therapy. TRAIL, a promising anti-tumor cytokine, induces apoptosis in tumor cells with low toxicity to normal cells. However, its off-target toxicity and limited stability have limited its clinical progress. Here, we engineered macrophages with Mono-TRAIL and Tri-TRAIL and found that Tri-TRAIL had higher cytotoxic activity against tumor cells than Mono-TRAIL in vitro. To target the tumor microenvironment (TME), we generated macrophages secreting trimeric TRAIL (Tri-TRAIL-iM) induced by the TME-specific promoter Arg1. The Tri-TRAIL-iM cells displayed high specific activatable activity in cell-based co-culture assay and tumor-baring mice models. In addition, we demonstrated that compared to macrophages over-expressing TRAIL under a non-inducible promoter, Tri-TRAIL-iM could more effectively induce apoptosis in cancer cells, inhibit tumor growth, and reduce systemic side effects. This strategy of inducing TRAIL delivery holds great potential for cancer therapy. It is promising to be combined with other engineering methods to maximize the therapeutic effects of solid tumors.

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来源期刊
Cellular immunology
Cellular immunology 生物-免疫学
CiteScore
8.20
自引率
2.30%
发文量
102
审稿时长
30 days
期刊介绍: Cellular Immunology publishes original investigations concerned with the immunological activities of cells in experimental or clinical situations. The scope of the journal encompasses the broad area of in vitro and in vivo studies of cellular immune responses. Purely clinical descriptive studies are not considered. Research Areas include: • Antigen receptor sites • Autoimmunity • Delayed-type hypersensitivity or cellular immunity • Immunologic deficiency states and their reconstitution • Immunologic surveillance and tumor immunity • Immunomodulation • Immunotherapy • Lymphokines and cytokines • Nonantibody immunity • Parasite immunology • Resistance to intracellular microbial and viral infection • Thymus and lymphocyte immunobiology • Transplantation immunology • Tumor immunity.
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