Engineered Endosymbionts that Modulate Primary Macrophage Function and Attenuate Tumor Growth by Shifting the Tumor Microenvironment.

IF 4.6 Q2 MATERIALS SCIENCE, BIOMATERIALS
Cody S Madsen, Ashley V Makela, Chima V Maduka, Emily M Greeson, Anthony Tundo, Evran Ural, Satyajit Hari Kulkarni, Ahmed A Zarea, Matti Kiupel, Maryam Sayadi, Christopher H Contag
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Abstract

Modulating gene expression in macrophages can be used to improve tissue regeneration and redirect tumor microenvironments (TMEs) toward positive therapeutic outcomes. We have developed Bacillus subtilis as an engineered endosymbiont (EES) capable of residing inside the eukaryotic host cell cytoplasm and controlling the fate of macrophages. Secretion of mammalian transcription factors (TFs) from B. subtilis that expresses listeriolysin O (LLO; allowing the EES to escape destruction by the macrophage) modulated expression of surface markers, cytokines, and chemokines, indicating functional changes in a macrophage/monocyte cell line. The engineered B. subtilis LLO TF strains were evaluated in murine bone marrow-derived macrophages (BMDMs) by flow cytometry, chemokine/cytokine profiling, metabolic assays, and RNA-Seq delivery of TFs by the EES shifted BMDM gene expression, production of cytokine and chemokines, and metabolic patterns, indicating that the TF strains could guide primary macrophage function. Thereafter, the ability of the TF strains to alter the TME was characterized in vivo in an orthotopic murine model of triple-negative breast cancer to assess therapeutic effects. The TF strains altered the TME by shifting immune cell composition and attenuating tumor growth. Additionally, multiple doses of the TF strains were well-tolerated by the mice. The use of B. subtilis LLO TF strains as EES showed promise as a unique cancer immunotherapy by directing the immune function intracellularly. The uses of EES could be expanded to modulate other mammalian cells over a range of biomedical applications.

通过改变肿瘤微环境调节原代巨噬细胞功能和减弱肿瘤生长的工程内共生物质。
调节巨噬细胞中的基因表达可用于改善组织再生,并将肿瘤微环境(TMEs)转向积极的治疗结果。我们已经开发出枯草芽孢杆菌作为一种工程内共生体(EES),能够驻留在真核宿主细胞质内并控制巨噬细胞的命运。表达李斯特菌素O (LLO)的枯草芽孢杆菌分泌哺乳动物转录因子(TFs)使EES逃脱巨噬细胞的破坏)调节了表面标记物、细胞因子和趋化因子的表达,表明巨噬细胞/单核细胞系的功能变化。通过流式细胞术、趋化因子/细胞因子谱分析、代谢分析和RNA-Seq法对工程枯草芽孢杆菌LLO TF菌株在小鼠骨髓源性巨噬细胞(BMDM)中的表达进行了评估,EES改变了BMDM基因的表达、细胞因子和趋化因子的产生以及代谢模式,表明TF菌株可以指导原发性巨噬细胞功能。随后,在原位三阴性乳腺癌小鼠模型中,研究了TF菌株改变TME的能力,以评估治疗效果。TF菌株通过改变免疫细胞组成和抑制肿瘤生长来改变TME。此外,多剂量的TF菌株对小鼠具有良好的耐受性。利用枯草芽孢杆菌LLO TF菌株作为EES,通过指导细胞内免疫功能,有望成为一种独特的癌症免疫治疗方法。EES的用途可以扩展到在一系列生物医学应用中调节其他哺乳动物细胞。
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来源期刊
ACS Applied Bio Materials
ACS Applied Bio Materials Chemistry-Chemistry (all)
CiteScore
9.40
自引率
2.10%
发文量
464
期刊介绍: ACS Applied Bio Materials is an interdisciplinary journal publishing original research covering all aspects of biomaterials and biointerfaces including and beyond the traditional biosensing, biomedical and therapeutic applications. The journal is devoted to reports of new and original experimental and theoretical research of an applied nature that integrates knowledge in the areas of materials, engineering, physics, bioscience, and chemistry into important bio applications. The journal is specifically interested in work that addresses the relationship between structure and function and assesses the stability and degradation of materials under relevant environmental and biological conditions.
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