BTN3A1 expressed in cervical cancer cells promotes Vγ9Vδ2 T cells exhaustion through upregulating transcription factors NR4A2/3 downstream of TCR signaling.

IF 8.2 2区生物学 Q1 CELL BIOLOGY

Cell Communication and Signaling Pub Date : 2024-09-28 DOI:10.1186/s12964-024-01834-0

Jian Liu, Min Wu, Yifan Yang, Xinyu Mei, Liming Wang, Jingyu Wang, Zixuan Wang, Shan He, Hangyu Liu, Han Jiang, Shen Qu, Yuwei Zhang, Ying Chen, Xun Tian, Yafei Huang, Hui Wang

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引用次数: 0

Abstract

Background: Clinical trials have shown that immunotherapy based on Vγ9Vδ2 T cells (Vδ2 T cells) is safe and well-tolerated for various cancers including cervical cancer (CC), but its overall treatment efficacy remains limited. Therefore, exploring the mechanisms underlying the suboptimal efficacy of Vδ2 T cell-based cancer immunotherapy is crucial for enabling its successful clinical translation.

Methods: Tumor samples from CC patients and CC cell line-derived xenograft (CDX) mice were analyzed using flow cytometry to examine the exhausted phenotype of tumor-infiltrating Vδ2 T cells. The interrelationship between BTN3A1 expression and Vδ2 T cells in CC, along with their correlation with patient prognosis, was analyzed using data from The Cancer Genome Atlas (TCGA) database. CC cell lines with BTN3A1 knockout (KO) and overexpression (OE) were constructed through lentivirus transduction, which were then co-cultured with expanded Vδ2 T cells, followed by detecting the function of Vδ2 T cells using flow cytometry. The pathways and transcription factors (TFs) related to BTN3A1-induced Vδ2 T cells exhaustion and the factors affecting BTN3A1 expression were identified by RNA-seq analysis, which was confirmed by flow cytometry, Western Blot, and gene manipulation.

Results: Tumor-infiltrating Vδ2 T cells exhibited an exhausted phenotype in both CC patients and CDX mice. BTN3A1 expressed in CC is highly enhancing exhaustion markers, while reducing the secretion of effector molecules in Vδ2 T cells. Blocking TCR or knocking down nuclear receptor subfamily 4 group A (NR4A) 2/3 can reverse BTN3A1-induced exhaustion in Vδ2 T cells. On the other hand, IFN-γ secreted by Vδ2 T cells promoted the expression of BTN3A1 and PD-L1.

Conclusions: Through binding γδ TCRs, BTN3A1 expressed on tumor cells, which is induced by IFN-γ, can promote Vδ2 T cells to upregulate the expression of TFs NR4A2/3, thereby affecting their activation and expression of exhaustion-related molecules in the tumor microenvironment (TME). Therefore, targeting BTN3A1 might overcome the immunosuppressive effect of the TME on Vδ2 T cells in CC.

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宫颈癌细胞中表达的 BTN3A1 通过上调 TCR 信号下游的转录因子 NR4A2/3 促进 Vγ9Vδ2 T 细胞衰竭。

背景：临床试验表明，基于Vγ9Vδ2 T细胞（Vδ2 T细胞）的免疫疗法对包括宫颈癌（CC）在内的多种癌症安全且耐受性良好，但其总体疗效仍然有限。因此，探索基于Vδ2 T细胞的癌症免疫疗法疗效不理想的机制对其临床转化至关重要：方法：使用流式细胞术分析了CC患者和CC细胞系衍生异种移植（CDX）小鼠的肿瘤样本，研究了肿瘤浸润Vδ2 T细胞的衰竭表型。利用癌症基因组图谱（TCGA）数据库的数据分析了BTN3A1表达和Vδ2 T细胞在CC中的相互关系，以及它们与患者预后的相关性。研究人员通过慢病毒转导构建了BTN3A1基因敲除（KO）和过表达（OE）的CC细胞系，然后将其与扩增的Vδ2 T细胞共培养，并使用流式细胞术检测Vδ2 T细胞的功能。通过RNA-seq分析确定了与BTN3A1诱导Vδ2 T细胞衰竭相关的途径和转录因子（TFs），以及影响BTN3A1表达的因素，并通过流式细胞术、Western Blot和基因操作进行了证实：结果：CC患者和CDX小鼠的肿瘤浸润Vδ2 T细胞均表现出衰竭表型。在CC中表达的BTN3A1能高度增强衰竭标志物，同时减少Vδ2 T细胞效应分子的分泌。阻断 TCR 或敲除核受体亚族 4 A 组（NR4A）2/3 可逆转 BTN3A1 诱导的 Vδ2 T 细胞衰竭。另一方面，Vδ2 T 细胞分泌的 IFN-γ 促进了 BTN3A1 和 PD-L1 的表达：结论：IFN-γ诱导的肿瘤细胞上表达的BTN3A1通过与γδ TCR结合，可促进Vδ2 T细胞上调TFs NR4A2/3的表达，从而影响其在肿瘤微环境（TME）中的活化和衰竭相关分子的表达。因此，靶向 BTN3A1 可能会克服 TME 对 CC 中 Vδ2 T 细胞的免疫抑制作用。

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来源期刊

Cell Communication and Signaling CELL BIOLOGY-

CiteScore

11.00

自引率

0.00%

发文量

180

期刊介绍： Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior. Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.