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代谢程序驱动治疗性 NK 细胞在缺氧肿瘤微环境中的功能。

Metabolic programs drive function of therapeutic NK cells in hypoxic tumor environments.

机构信息

Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.

Xcell Biosciences, San Francisco, CA, USA.

出版信息

Sci Adv. 2024 Nov;10(44):eadn1849. doi: 10.1126/sciadv.adn1849. Epub 2024 Oct 30.

DOI:10.1126/sciadv.adn1849
PMID:39475618
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11524192/
Abstract

Limited oxygen (hypoxia) in solid tumors poses a challenge to successful immunotherapy with natural killer (NK) cells. NK cells have impaired cytotoxicity when cultured in hypoxia (1% oxygen) but not physiologic (>5%) or atmospheric oxygen (20%). We found that changes to cytotoxicity were regulated at the transcriptional level and accompanied by metabolic dysregulation. Dosing with interleukin-15 (IL-15) enhanced NK cell cytotoxicity in hypoxia, but preactivation with feeder cells bearing IL-21 and 4-1BBL was even better. Preactivation resulted in less perturbed metabolism in hypoxia; greater resistance to oxidative stress; and no hypoxia-induced loss of transcription factors (T-bet and Eomes), activating receptors, adhesion molecules (CD2), and cytotoxic proteins (TRAIL and FasL). There remained a deficit in CD122/IL-2Rβ when exposed to hypoxia, which affected IL-15 signaling. However, tri-specific killer engager molecules that deliver IL-15 in the context of anti-CD16/FcγRIII were able to bypass this deficit, enhancing cytotoxicity of both fresh and preactivated NK cells in hypoxia.

摘要

实体肿瘤中的有限氧气（缺氧）对自然杀伤 (NK) 细胞的成功免疫治疗构成了挑战。NK 细胞在低氧（1%氧气）而非生理（>5%）或大气氧气（20%）中培养时，细胞毒性会受损。我们发现细胞毒性的变化受转录水平调节，并伴有代谢失调。白细胞介素-15 (IL-15) 的剂量可以增强 NK 细胞在低氧中的细胞毒性，但用带有 IL-21 和 4-1BBL 的饲养细胞预先激活效果更好。预先激活导致低氧代谢失调减少；对氧化应激的抵抗力增强；并且不会诱导转录因子（T-bet 和 Eomes）、激活受体、粘附分子（CD2）和细胞毒性蛋白（TRAIL 和 FasL）丢失。当暴露于低氧时，仍然存在 CD122/IL-2Rβ 的缺陷，这会影响 IL-15 信号转导。然而，三特异性杀伤剂衔接分子能够在抗 CD16/FcγRIII 的情况下传递 IL-15，从而绕过这一缺陷，增强新鲜和预先激活的 NK 细胞在低氧中的细胞毒性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3ef/11524192/e9fad8494b7a/sciadv.adn1849-f10.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3ef/11524192/cf5b5434f4a6/sciadv.adn1849-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3ef/11524192/f4c8f840d3ec/sciadv.adn1849-f9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3ef/11524192/e9fad8494b7a/sciadv.adn1849-f10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3ef/11524192/a494d49b69f1/sciadv.adn1849-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3ef/11524192/07a810086825/sciadv.adn1849-f2.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3ef/11524192/e57887b763a5/sciadv.adn1849-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3ef/11524192/bb065c9c1133/sciadv.adn1849-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3ef/11524192/aa6e1fc4b808/sciadv.adn1849-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3ef/11524192/06268172f53d/sciadv.adn1849-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3ef/11524192/cf5b5434f4a6/sciadv.adn1849-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3ef/11524192/f4c8f840d3ec/sciadv.adn1849-f9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f3ef/11524192/e9fad8494b7a/sciadv.adn1849-f10.jpg

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2
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EBioMedicine. 2023 Oct;96:104811. doi: 10.1016/j.ebiom.2023.104811. Epub 2023 Sep 21.
3
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Cell Mol Immunol. 2025 May 23. doi: 10.1038/s41423-025-01297-4.
4
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5
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