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基于 IFN-γ 和 TNF-α 协同诱导高表达 CXCL10，构建了自我驾驶的抗-αFR CAR 工程化 NK 细胞。

Construction of self-driving anti-αFR CAR-engineered NK cells based on IFN-γ and TNF-α synergistically induced high expression of CXCL10.

机构信息

Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China; Department of Gynecology and Obstetrics, The 958th Hospital, Southwest Hospital, Army Medical University, Chongqing, China.

Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing, China; Department of orthopedics, 953 Hospital of PLA Army, Shigatse Branch of Xinqiao Hospital, Army Medical University, Shigatse, China.

出版信息

Neoplasia. 2024 Dec;58:101065. doi: 10.1016/j.neo.2024.101065. Epub 2024 Oct 3.

DOI:10.1016/j.neo.2024.101065
PMID:39366148
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11489333/
Abstract

INTRODUCTION: Ovarian cancer is the most malignant gynecological tumor. Previous studies have demonstrated that chimeric antigen receptor (CAR)-engineered NK-92 cells targeting folate receptor α (αFR) (NK-92-αFR-CAR) can specifically kill αFR-positive ovarian cancer cells. However, the migration barrier restricts antitumor effects of CAR-engineered cells. OBJECTIVES: To elucidate the mechanism by which NK-92-αFR-CAR cells induce the secretion of chemokine CXCL10 during killing ovarian cancer cells. It is speculated that NK-92-αFR-CAR-CXCR3A can target αFR and have chemotaxis of CXCL10, and they may have stronger killing effect of ovarian cancer. METHODS: Study the mechanism of CXCL10 expression strongly induced by TNF-α and IFN-γ combined stimulation in ovarian cancer cells. Construct the fourth generation of NK-92-αFR-CAR-CXCR3A cells, which were co-expressed CXCR3A and αFR-CAR. Evaluate the killing and migration effects of NK-92-αFR-CAR-CXCR3A in vitro and in vivo. RESULTS: RNA sequencing (RNA-seq) first revealed that the expression level of the chemokine CXCL10 was most significantly increased in ovarian cancer cells co-cultured with NK-92-αFR-CAR. Secondly, cytokine stimulation experiments confirmed that IFN-γ and TNF-α secreted by NK-92-αFR-CAR synergistically induced high CXCL10 expression in ovarian cancer cells. Further signaling pathway experiments showed that IFN-γ and TNF-α enhanced the activation level of the IFN-γ-IFNGR-JAK1/2-STAT1-CXCL10 signaling axis. Cytotoxicity experiments showed that NK-92-αFR-CAR-CXCR3A cells could not only efficiently kill αFR-positive ovarian cancer cells in vitro but also secrete IFN-γ and TNF-α. Higher migration than that of NK-92-αFR-CAR was detected in NK-92-αFR-CAR-CXCR3A using transwell assay. NK-92-αFR-CAR-CXCR3A effectively killed tumor cells in different mouse xenograft models of ovarian cancer and increased infiltration into tumor tissue. CONCLUSION: This study confirmed that IFN-γ and TNF-α secreted by αFR-CAR-engineered NK cells can synergistically induce high expression of CXCL10 in ovarian cancer cells and constructed self-driving αFR-CAR-engineered NK cells that can break through migration barriers based on CXCL10, which may provide a new therapeutic weapon for ovarian cancer.

摘要

简介：卵巢癌是最恶性的妇科肿瘤。先前的研究表明，靶向叶酸受体α（αFR）的嵌合抗原受体（CAR）修饰的 NK-92 细胞（NK-92-αFR-CAR）可以特异性杀伤αFR 阳性卵巢癌细胞。然而，迁移障碍限制了 CAR 修饰细胞的抗肿瘤作用。

目的：阐明 NK-92-αFR-CAR 细胞在杀伤卵巢癌细胞过程中诱导趋化因子 CXCL10 分泌的机制。推测 NK-92-αFR-CAR-CXCR3A 可以靶向 αFR 并具有 CXCL10 的趋化性，它们可能对卵巢癌具有更强的杀伤作用。

方法：研究 TNF-α和 IFN-γ联合刺激诱导卵巢癌细胞强烈表达 CXCL10 的机制。构建共表达 CXCR3A 和 αFR-CAR 的第四代 NK-92-αFR-CAR-CXCR3A 细胞。评估 NK-92-αFR-CAR-CXCR3A 在体外和体内的杀伤和迁移作用。

结果：RNA 测序（RNA-seq）首先揭示了在与 NK-92-αFR-CAR 共培养的卵巢癌细胞中，趋化因子 CXCL10 的表达水平显著增加。其次，细胞因子刺激实验证实 NK-92-αFR-CAR 分泌的 IFN-γ和 TNF-α协同诱导卵巢癌细胞高表达 CXCL10。进一步的信号通路实验表明，IFN-γ和 TNF-α增强了 IFN-γ-IFNGR-JAK1/2-STAT1-CXCL10 信号轴的激活水平。细胞毒性实验表明，NK-92-αFR-CAR-CXCR3A 细胞不仅能有效杀伤体外 αFR 阳性卵巢癌细胞，还能分泌 IFN-γ和 TNF-α。与 NK-92-αFR-CAR 相比，NK-92-αFR-CAR-CXCR3A 在 Transwell 测定中检测到更高的迁移率。NK-92-αFR-CAR-CXCR3A 在不同卵巢癌小鼠异种移植模型中有效杀伤肿瘤细胞，并增加向肿瘤组织的浸润。

结论：本研究证实，αFR-CAR 修饰 NK 细胞分泌的 IFN-γ和 TNF-α可以协同诱导卵巢癌细胞高表达 CXCL10，并构建了基于 CXCL10 突破迁移障碍的自驱动 αFR-CAR 修饰 NK 细胞，这可能为卵巢癌提供一种新的治疗武器。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5df7/11489333/adfcd7b723ce/gr8.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5df7/11489333/b8fde00285b2/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5df7/11489333/a351d1d1f449/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5df7/11489333/7a58d75fae3e/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5df7/11489333/0fec5987225a/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5df7/11489333/e2c9ad6f3613/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5df7/11489333/1e3fc8465b45/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5df7/11489333/cd1f99a088eb/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5df7/11489333/adfcd7b723ce/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5df7/11489333/f8ed7e5a154e/ga1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5df7/11489333/b8fde00285b2/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5df7/11489333/a351d1d1f449/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5df7/11489333/7a58d75fae3e/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5df7/11489333/0fec5987225a/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5df7/11489333/e2c9ad6f3613/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5df7/11489333/1e3fc8465b45/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5df7/11489333/cd1f99a088eb/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5df7/11489333/adfcd7b723ce/gr8.jpg

相似文献

[1]
Construction of self-driving anti-αFR CAR-engineered NK cells based on IFN-γ and TNF-α synergistically induced high expression of CXCL10.

Neoplasia. 2024-12

[2]
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本文引用的文献

[1]
Cancer statistics, 2022.

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[2]
Tandem CAR-T cells targeting FOLR1 and MSLN enhance the antitumor effects in ovarian cancer.

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TNF-α augments CXCL10/CXCR3 axis activity to induce Epithelial-Mesenchymal Transition in colon cancer cell.

Int J Biol Sci. 2021

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Ann Transl Med. 2020-12

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CXCR1 Expression to Improve Anti-Cancer Efficacy of Intravenously Injected CAR-NK Cells in Mice with Peritoneal Xenografts.

Mol Ther Oncolytics. 2019-12-24

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CXCL11 promotes tumor progression by the biased use of the chemokine receptors CXCR3 and CXCR7.

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[7]
Anti-αFR CAR-engineered NK-92 Cells Display Potent Cytotoxicity Against αFR-positive Ovarian Cancer.

J Immunother. 2019-10

[8]
CAR T-Cells Targeting the Integrin αvβ6 and Co-Expressing the Chemokine Receptor CXCR2 Demonstrate Enhanced Homing and Efficacy against Several Solid Malignancies.

Cancers (Basel). 2019-5-14

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microRNA and mRNA profiles in the amygdala are associated with stress-induced depression and resilience in juvenile mice.

Psychopharmacology (Berl). 2019-3-21

[10]
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Hematol Oncol Clin North Am. 2018-12

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