Uptake of long-chain fatty acids from the bone marrow suppresses CD8+ T-cell metabolism and function in multiple myeloma.
Uptake of long-chain fatty acids from the bone marrow suppresses CD8+ T-cell metabolism and function in multiple myeloma.
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DOI：
10.1182/bloodadvances.2023009890
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发表时间：
2023-10-24
期刊：
影响因子：
7.5
通讯作者：
中科院分区：
文献类型：
--
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MM 骨髓中的 CD8+ T 细胞功能和线粒体质量下降，并且低于匹配的外周血。这些变化与长链脂肪酸的摄取有关，并且可以通过阻断脂质转运蛋白 FATP1 来恢复 T 细胞功能。 T 细胞在多发性骨髓瘤 (MM) 中表现出功能受损，但骨髓微环境中的抑制机制仍不清楚。我们观察到，与对照组相比，多发性骨髓瘤患者的骨髓 CD8+ T 细胞功能下降，并且骨髓样本中的 CD8+ T 细胞功能也始终低于匹配的外周血样本。这些变化伴随着线粒体质量的减少和长链脂肪酸摄取的显着增加。体外模型证实，骨髓脂质的摄取会抑制 CD8+ T 功能，该功能在自体骨髓血浆中受损，但通过脂质去除可以恢复。单细胞 RNA 测序数据分析确定了 MM 骨髓 CD8+ T 细胞中脂肪酸转运蛋白 1 (FATP1) 的表达，并且 FATP1 阻断也挽救了 CD8+ T 细胞功能，从而将其确定为增强 MM 中 T 细胞活性的新靶点。最后，对接受治疗的患者队列样本进行分析发现，CD8+ T 细胞代谢功能障碍在对治疗有反应的 MM 患者中得到缓解，但在复发性 MM 患者中则没有，并且与 T 细胞功能的实质性恢复相关。
CD8+ T-cell function and mitochondrial mass decline in the bone marrow in MM and are lower than in matched peripheral blood. These changes are linked to uptake of long-chain fatty acids, and T-cell function can be rescued by blockade of the lipid transporter FATP1. T cells demonstrate impaired function in multiple myeloma (MM) but suppressive mechanisms in the bone marrow microenvironment remain poorly defined. We observe that bone marrow CD8+ T-cell function is decreased in MM compared with controls, and is also consistently lower within bone marrow samples than in matched peripheral blood samples. These changes are accompanied by decreased mitochondrial mass and markedly elevated long-chain fatty acid uptake. In vitro modeling confirmed that uptake of bone marrow lipids suppresses CD8+ T function, which is impaired in autologous bone marrow plasma but rescued by lipid removal. Analysis of single-cell RNA-sequencing data identified expression of fatty acid transport protein 1 (FATP1) in bone marrow CD8+ T cells in MM, and FATP1 blockade also rescued CD8+ T-cell function, thereby identifying this as a novel target to augment T-cell activity in MM. Finally, analysis of samples from cohorts of patients who had received treatment identified that CD8+ T-cell metabolic dysfunction resolves in patients with MM who are responsive to treatment but not in patients with relapsed MM, and is associated with substantial T-cell functional restoration.
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影响因子：
64.5
作者：
Chang CH;Curtis JD;Maggi LB Jr;Faubert B;Villarino AV;O'Sullivan D;Huang SC;van der Windt GJ;Blagih J;Qiu J;Weber JD;Pearce EJ;Jones RG;Pearce EL
通讯作者：
Pearce EL
影响因子：
64.5
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通讯作者：
Kaech SM
影响因子：
11.5
作者：
Kwon, Minsuk;Kim, Chang Gon;Shin, Eui-Cheol
通讯作者：
Shin, Eui-Cheol
影响因子：
3.7
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Perdomo G
影响因子：
12.8
作者：
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通讯作者：
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