Nanoparticle-Mediated Lipid Metabolic Reprogramming of T Cells in Tumor Microenvironments for Immunometabolic Therapy,Nano-Micro Letters

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Nanoparticle-Mediated Lipid Metabolic Reprogramming of T Cells in Tumor Microenvironments for Immunometabolic Therapy
Nano-Micro Letters ( IF 31.6 ) Pub Date : 2021-01-04 , DOI: 10.1007/s40820-020-00555-6
Dongyoon Kim ₁ , Yina Wu ₁ , Qiaoyun Li ₁ , Yu-Kyoung Oh ₁

Affiliation

Highlights

aCD3/F/AN, anti-CD3e f(ab′)2 fragment-modified and fenofibrate-encapsulated amphiphilic nanoparticle, reprogrammed mitochondrial lipid metabolism of T cells.
aCD3/F/AN specifically activated T cells in glucose-deficient conditions mimicking tumor microenvironment, and exerted an effector killing effect against tumor cells.
In vivo treatment with aCD3/F/AN increased T cell infiltration, cytokine production, and prevented tumor growth.

Abstract

We report the activation of anticancer effector functions of T cells through nanoparticle-induced lipid metabolic reprogramming. Fenofibrate was encapsulated in amphiphilic polygamma glutamic acid-based nanoparticles (F/ANs), and the surfaces of F/ANs were modified with an anti-CD3e f(ab′)2 fragment, yielding aCD3/F/ANs. An in vitro study reveals enhanced delivery of aCD3/F/ANs to T cells compared with plain F/ANs. aCD3/F/AN-treated T cells exhibited clear mitochondrial cristae, a higher membrane potential, and a greater mitochondrial oxygen consumption rate under glucose-deficient conditions compared with T cells treated with other nanoparticle preparations. Peroxisome proliferator-activated receptor-α and downstream fatty acid metabolism-related genes are expressed to a greater extent in aCD3/F/AN-treated T cells. Activation of fatty acid metabolism by aCD3/F/ANs supports the proliferation of T cells in a glucose-deficient environment mimicking the tumor microenvironment. Real-time video recordings show that aCD3/F/AN-treated T cells exerted an effector killing effect against B16F10 melanoma cells. In vivo administration of aCD3/F/ANs can increase infiltration of T cells into tumor tissues. The treatment of tumor-bearing mice with aCD3/F/ANs enhances production of various cytokines in tumor tissues and prevented tumor growth. Our findings suggest the potential of nanotechnology-enabled reprogramming of lipid metabolism in T cells as a new modality of immunometabolic therapy.

中文翻译：

用于免疫代谢治疗的肿瘤微环境中 T 细胞的纳米颗粒介导的脂质代谢重编程

强调

aCD3/F/AN、抗 CD3e f(ab')2 片段修饰和非诺贝特包裹的两亲性纳米颗粒，重编程了 T 细胞的线粒体脂质代谢。
aCD3/F/AN 在模拟肿瘤微环境的葡萄糖缺乏条件下特异性激活 T 细胞，并对肿瘤细胞发挥效应杀伤作用。
用 aCD3/F/AN 进行体内治疗可增加 T 细胞浸润、细胞因子产生并阻止肿瘤生长。

抽象的

我们报告了通过纳米颗粒诱导的脂质代谢重编程激活 T 细胞的抗癌效应功能。非诺贝特被包裹在两亲性聚γ谷氨酸基纳米颗粒（F/ANs）中，并用抗CD3e f(ab')2片段修饰F/ANs的表面，产生aCD3/F/ANs。一项体外研究表明，与普通 F/ANs 相比，aCD3/F/ANs 向 T 细胞的递送增强。与用其他纳米颗粒制剂处理的 T 细胞相比，aCD3/F/AN 处理的 T 细胞在葡萄糖缺乏条件下表现出明显的线粒体嵴、更高的膜电位和更大的线粒体耗氧率。过氧化物酶体增殖物激活受体-α 和下游脂肪酸代谢相关基因在 aCD3/F/AN 处理的 T 细胞中表达程度更高。aCD3/F/ANs 激活脂肪酸代谢支持 T 细胞在模拟肿瘤微环境的葡萄糖缺乏环境中增殖。实时视频记录显示，aCD3/F/AN 处理的 T 细胞对 B16F10 黑色素瘤细胞具有效应杀伤作用。aCD3/F/ANs 的体内给药可以增加 T 细胞向肿瘤组织的浸润。用 aCD3/F/ANs 治疗荷瘤小鼠可增强肿瘤组织中各种细胞因子的产生并阻止肿瘤生长。我们的研究结果表明，纳米技术支持的 T 细胞脂质代谢重编程作为一种新的免疫代谢治疗方式的潜力。实时视频记录显示，aCD3/F/AN 处理的 T 细胞对 B16F10 黑色素瘤细胞具有效应杀伤作用。aCD3/F/ANs 的体内给药可以增加 T 细胞向肿瘤组织的浸润。用 aCD3/F/ANs 治疗荷瘤小鼠可增强肿瘤组织中各种细胞因子的产生并阻止肿瘤生长。我们的研究结果表明，纳米技术支持的 T 细胞脂质代谢重编程作为一种新的免疫代谢治疗方式的潜力。实时视频记录显示，aCD3/F/AN 处理的 T 细胞对 B16F10 黑色素瘤细胞具有效应杀伤作用。aCD3/F/ANs 的体内给药可以增加 T 细胞向肿瘤组织的浸润。用 aCD3/F/ANs 治疗荷瘤小鼠可增强肿瘤组织中各种细胞因子的产生并阻止肿瘤生长。我们的研究结果表明，纳米技术支持的 T 细胞脂质代谢重编程作为一种新的免疫代谢治疗方式的潜力。

更新日期：2021-01-04

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