ATM-AMPKα介导的LAG-3表达抑制癌症前列腺T细胞功能。

IF 3.7 4区 医学 Q2 CELL BIOLOGY Cellular immunology Pub Date : 2023-09-28 DOI:10.1016/j.cellimm.2023.104773
Xinyao Zhang , Haiqi Chen , Jiawen Han , Zongren Wang , Yu Guo , Zhongyang Zhou , Rong Luo , Meiqin Dai , Wei Ou , Lingwu Chen , Lan Shao
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引用次数: 0

摘要

癌症的免疫治疗面临着严峻的挑战。因此,必须阐明调节前列腺癌T细胞功能的共抑制受体。在这里,我们发现抑制性受体LAG3在前列腺癌患者的T细胞中被显著诱导。基因阵列分析显示,PCa T细胞中共济失调-毛细血管扩张症突变(ATM)基因表达不足是LAG3表达升高的原因。从机制上讲,ATM表达不足削弱了其激活AMPKα信号传导和CD4+T细胞功能的能力,这进一步增强了转录因子XBP1和EGR2与LAG3启动子的结合。PCa T细胞中ATM的重组和XBP1或EGR2的抑制抑制了LAG3的表达,并恢复了来自PCa的CD4+T细胞的效应器功能。我们的研究揭示了前列腺癌患者CD4+T淋巴细胞LAG3上调的机制,并可能为开发前列腺癌治疗的免疫治疗策略提供见解。
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ATM-AMPKα mediated LAG-3 expression suppresses T cell function in prostate cancer

Immunotherapy for prostate cancer (PCa) faces serious challenges. Therefore, the co-inhibitory receptors that regulate T cell function of PCa must be elucidated. Here we identified that the inhibitory receptor LAG3 was significantly induced in T cells from PCa patients. Gene array analysis revealed that insufficient ataxia telangiectasia mutated (ATM) gene expression in PCa T cells was responsible for the elevated LAG3 expression. Mechanistically, insufficient ATM expression impaired its ability to activate AMPKα signaling and CD4+ T cell functions, which further enhances the binding of the transcription factors XBP1 and EGR2 to LAG3 promoter. Reconstitution of ATM and inhibition of XBP1 or EGR2 in PCa T cells suppressed LAG3 expression and restored the effector function of CD4+ T cells from PCa. Our study revealed the mechanism of LAG3 upregulation in CD4+ T lymphocytes of PCa patients and may provide insights for the development of immunotherapeutic strategies for PCa treatment.

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来源期刊
Cellular immunology
Cellular immunology 生物-免疫学
CiteScore
8.20
自引率
2.30%
发文量
102
审稿时长
30 days
期刊介绍: Cellular Immunology publishes original investigations concerned with the immunological activities of cells in experimental or clinical situations. The scope of the journal encompasses the broad area of in vitro and in vivo studies of cellular immune responses. Purely clinical descriptive studies are not considered. Research Areas include: • Antigen receptor sites • Autoimmunity • Delayed-type hypersensitivity or cellular immunity • Immunologic deficiency states and their reconstitution • Immunologic surveillance and tumor immunity • Immunomodulation • Immunotherapy • Lymphokines and cytokines • Nonantibody immunity • Parasite immunology • Resistance to intracellular microbial and viral infection • Thymus and lymphocyte immunobiology • Transplantation immunology • Tumor immunity.
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