γδ T 细胞调节小细胞肺癌中的抗肿瘤免疫
γδ T cells modulate anti-tumor immunity in small cell lung cancer.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
γδTCR 和 TLR7/8 的共刺激通过调节 mTOR 通路和 APC 功能促进 Vδ2 T 细胞的抗肿瘤活性
英文原题：Costimulation of γδTCR and TLR7/8 promotes Vδ2 T-cell antitumor activity by modulating mTOR pathway and APC function.
查看英文原题
Costimulation of γδTCR and TLR7/8 promotes Vδ2 T-cell antitumor activity by modulating mTOR pathway and APC function.
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研究概要
由 IPP 和 resiquimod 扩增的 Vδ2 T 细胞显示出改善的抗肿瘤功能，并具有提高基于γδ T 细胞疗法疗效的潜力。
研究思路结论见上方概要
背景
γδ T 细胞是肿瘤免疫治疗中具有吸引力的效应细胞。由唑来膦酸（ZOL）扩增的 Vδ2 T 细胞是过继性细胞治疗中最常用的 γδ T 细胞。然而，过继转移扩增的 Vδ2 T 细胞临床疗效有限。
方法
我们开发了一种通过分别使用异戊烯基焦磷酸（IPP）和雷西莫特激活γδT细胞受体（γδTCR）和Toll样受体（TLR）7/8，从而在PBMCs中扩增Vδ2 T细胞的共刺激方法，并在体外二维和三维球体模型及体内模型中测试了功能标志物和抗肿瘤效果。采用单细胞测序数据集分析和反相蛋白阵列进行机制研究。
结果
我们发现，经IPP联合resiquimod扩增的Vδ2 T细胞对肿瘤细胞的细胞毒性显著增强，且其PD-1表达低于经IPP或ZOL扩增的Vδ2 T细胞。在机制上，这种共刺激增强了磷脂酰肌醇3-激酶（PI3K）-蛋白激酶B（PKB/Akt）-哺乳动物雷帕霉素靶蛋白（mTOR）通路以及TLR7/8-MyD88通路的激活。Resiquimod以抗原呈递细胞依赖性和非依赖性两种方式刺激Vδ2 T细胞扩增。此外，在体外Vδ2 T细胞扩增过程中，resiquimod减少了黏附性抑制性抗原呈递细胞（APC）的数量，并通过降低这些细胞中PD-L1和细胞毒性T淋巴细胞相关蛋白4（CTLA-4）的表达来抑制APC的抑制功能。最后，我们证明使用IPP联合resiquimod或ZOL可以从人源化NSG小鼠的PBMC和脾脏中扩增人Vδ2 T细胞，表明人源化小鼠是研究人γδ T细胞发育和功能的有前景的临床前模型。
展开英文摘要原文
BACKGROUND
Gamma delta (γδ) T cells are attractive effector cells for cancer immunotherapy. Vδ2 T cells expanded by zoledronic acid (ZOL) are the most commonly used γδ T cells for adoptive cell therapy. However, adoptive transfer of the expanded Vδ2 T cells has limited clinical efficacy.
METHODS
We developed a costimulation method for expansion of Vδ2 T cells in PBMCs by activating γδ T-cell receptor (γδTCR) and Toll-like receptor (TLR) 7/8 using isopentenyl pyrophosphate (IPP) and resiquimod, respectively, and tested the functional markers and antitumoral effects in vitro two-dimensional two-dimensional and three-dimensional spheroid models and in vivo models. Single-cell sequencing dataset analysis and reverse-phase protein array were employed for mechanistic studies.
RESULTS
We find that Vδ2 T cells expanded by IPP plus resiquimod showed significantly increased cytotoxicity to tumor cells with lower programmed cell death protein 1 (PD-1) expression than Vδ2 T cells expanded by IPP or ZOL. Mechanistically, the costimulation enhanced the activation of the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB/Akt)-the mammalian target of rapamycin (mTOR) pathway and the TLR7/8-MyD88 pathway. Resiquimod stimulated Vδ2 T-cell expansion in both antigen presenting cell dependent and independent manners. In addition, resiquimod decreased the number of adherent inhibitory antigen-presenting cells (APCs) and suppressed the inhibitory function of APCs by decreasing PD-L1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression in these cells during in vitro Vδ2 T-cell expansion. Finally, we showed that human Vδ2 T cells can be expanded from PBMCs and spleen of humanized NSG mice using IPP plus resiquimod or ZOL, demonstrating that humanized mice are a promising preclinical model for studying human γδ T-cell development and function.
CONCLUSIONS
Vδ2 T cells expanded by IPP and resiquimod demonstrate improved anti-tumor function and have the potential to increase the efficacy of γδ T cell-based therapies.
论文信息
- 作者
- Wang H、Chen H、Liu S、Zhang J、Lu H、Somasundaram R、Choi R、Zhang G
- 第一作者单位
- Department of Pathology and Laboratory Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania, USA.United States
- 通讯作者单位
- Department of Pathology and Laboratory Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania, USA xug@pennmedicine.upenn.edu.United States
- 文献类型
- 美国 NIH 资助研究 · 非美国政府资助研究
- 期刊
- Journal for immunotherapy of cancer2021 Dec
- 原文标识
- PubMed 34937742 · DOI 10.1136/jitc-2021-003339
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