免疫检查点阻断通过扩增效应 CD8⁺ T 细胞克隆增强淋巴细胞清除性化疗诱导的抗肿瘤免疫
Immune Checkpoint Blockade Augments Lymphodepleting Chemotherapy-Induced Antitumor Immunity by Expanding Effector CD8+ T-cell Clones.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
FOXP3 表达使 CD8 T 细胞的代谢能力多样化并增强其在黑色素瘤过继免疫治疗中的疗效
英文原题：FOXP3 expression diversifies the metabolic capacity and enhances the efficacy of CD8 T cells in adoptive immunotherapy of melanoma.
查看英文原题
FOXP3 expression diversifies the metabolic capacity and enhances the efficacy of CD8 T cells in adoptive immunotherapy of melanoma.
分数与星级只用于站内排序 —— 不代表疗效、安全性或个人适用性。
中文摘要
调节性T细胞在肿瘤微环境（TME）中凭借FOXP3驱动的代谢程序，使其能够利用不同的代谢途径，从而压倒常规T细胞。利用过继性T细胞治疗（ACT）的黑色素瘤模型，我们发现成熟CD8 T细胞中FOXP3过表达可改善其抗肿瘤疗效，有利于其肿瘤招募、增殖和细胞毒性。过表达FOXP3（Foxp3UP）的CD8 T细胞表现出组织驻留记忆样和效应T细胞的特征，但无抑制活性。对肿瘤浸润Foxp3UP CD8 T细胞的转录组分析显示，糖酵解、脂肪酸（FA）代谢和氧化磷酸化（OXPHOS）等多种代谢途径呈正向富集。瘤内Foxp3UP CD8 T细胞表现出增强的葡萄糖和FA摄取能力以及细胞内脂质积累。有趣的是，Foxp3UP CD8 T细胞通过激活有氧糖酵解来补偿线粒体呼吸驱动ATP产生的缺失。
此外，在营养受限条件下，这些细胞利用FA氧化驱动OXPHOS以满足其能量需求。重要的是，它们偶联糖酵解和OXPHOS的能力使其能够在葡萄糖限制下维持增殖。
我们的发现证明了FOXP3在CD8 T细胞适应TME中一个此前未知的作用，这可能增强其在ACT中的疗效。
展开英文摘要原文
Regulatory T cells overwhelm conventional T cells in the tumor microenvironment (TME) thanks to a FOXP3-driven metabolic program that allows them to engage different metabolic pathways. Using a melanoma model of adoptive T cell therapy (ACT), we show that FOXP3 overexpression in mature CD8 T cells improved their antitumor efficacy, favoring their tumor recruitment, proliferation, and cytotoxicity. FOXP3-overexpressing (Foxp3UP) CD8 T cells exhibited features of tissue-resident memory-like and effector T cells, but not suppressor activity.
Transcriptomic analysis of tumor-infiltrating Foxp3UP CD8 T cells showed positive enrichment in a wide variety of metabolic pathways, such as glycolysis, fatty acid (FA) metabolism, and oxidative phosphorylation (OXPHOS). Intratumoral Foxp3UP CD8 T cells exhibited an enhanced capacity for glucose and FA uptake as well as accumulation of intracellular lipids. Interestingly, Foxp3UP CD8 T cells compensated for the loss of mitochondrial respiration-driven ATP production by activating aerobic glycolysis.
Moreover, in limiting nutrient conditions these cells engaged FA oxidation to drive OXPHOS for their energy demands.
Importantly, their ability to couple glycolysis and OXPHOS allowed them to sustain proliferation under glucose restriction.
Our findings demonstrate a hitherto unknown role for FOXP3 in the adaptation of CD8 T cells to TME that may enhance their efficacy in ACT.
论文信息
- 作者
- Conde E、Casares N、Mancheño U、Elizalde E、Vercher E、Capozzi R、Santamaria E、Rodriguez-Madoz JR
- 第一作者单位
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, Avenida Pio XII 55, Pamplona, 31008 Navarra, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Avenida Pio XII 55, Pamplona, 31008 Navarra, Spain.Spain
- 通讯作者单位
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, Avenida Pio XII 55, Pamplona, 31008 Navarra, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Avenida Pio XII 55, Pamplona, 31008 Navarra, Spain; CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain. Electronic address: mshervas@unav.es.Spain
- 文献类型
- 非美国政府资助研究
- 期刊
- Molecular therapy : the journal of the American Society of Gene Therapy2023 Jan 4
- 原文标识
- PubMed 36045586 · DOI 10.1016/j.ymthe.2022.08.017
在 PubMed 查看 → 出版商原文（DOI） 全文 PDF（PMC）· 可下载 治疗专题与资料阅读指南 资料来源与翻译说明 报告译文或资料问题 →