针对胃癌致癌融合基因 CLDN18-ARHGAP 的免疫疗法。

IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
EMBO Molecular Medicine Pub Date : 2024-09-01 Epub Date: 2024-08-20 DOI:10.1038/s44321-024-00120-3
Yue Wang, Hanbing Wang, Tao Shi, Xueru Song, Xin Zhang, Yue Zhang, Xuan Wang, Keying Che, Yuting Luo, Lixia Yu, Baorui Liu, Jia Wei
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引用次数: 0

摘要

CLDN18-ARHGAP融合基因是胃癌中新发现的致癌驱动基因。本中心在9%(8/87)的胃癌患者中检测到了该基因。我们生成了一种特异性靶向 CLDN18-ARHGAP 融合基因的免疫原性多肽来诱导新抗原反应性 T 细胞,在体外细胞培养模型和体内异种移植胃癌模型中均被证明具有特异性和强大的抗肿瘤能力。除了免疫原性潜力外,研究还发现CLDN18-ARHGAP融合基因还能通过诱导调节性T(Treg)细胞富集的微环境来促进免疫抑制。从机制上讲,CLDN18-ARHGAP融合基因的胃癌细胞会激活PI3K/AKT-mTOR-FAS信号转导,从而增强胃癌细胞的游离脂肪酸生成,有利于Treg细胞的存活。此外,抑制 PI3K 可有效逆转 Treg 细胞的上调,从而增强体外新抗原反应 T 细胞的抗肿瘤细胞毒性,并降低异种移植胃癌模型中的肿瘤生长。我们的研究发现,CLDN18-ARHGAP融合基因是免疫原性新表位的重要来源,是肿瘤免疫微环境的关键调节因子,以及针对这种致癌融合基因的免疫治疗应用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Immunotherapies targeting the oncogenic fusion gene CLDN18-ARHGAP in gastric cancer.

The CLDN18-ARHGAP fusion gene is an oncogenic driver newly discovered in gastric cancer. It was detected in 9% (8/87) of gastric cancer patients in our center. An immunogenic peptide specifically targeting CLDN18-ARHGAP fusion gene was generated to induce neoantigen-reactive T cells, which was proved to have specific and robust anti-tumor capacity both in in vitro coculture models and in vivo xenograft gastric cancer models. Apart from the immunogenic potential, CLDN18-ARHGAP fusion gene was also found to contribute to immune suppression by inducing a regulatory T (Treg) cell-enriched microenvironment. Mechanistically, gastric cancer cells with CLDN18-ARHGAP fusion activate PI3K/AKT-mTOR-FAS signaling, which enhances free fatty acid production of gastric cancer cells to favor the survival of Treg cells. Furthermore, PI3K inhibition could effectively reverse Treg cells upregulation to enhance anti-tumor cytotoxicity of neoantigen-reactive T cells in vitro and reduce tumor growth in the xenograft gastric cancer model. Our study identified the CLDN18-ARHGAP fusion gene as a critical source of immunogenic neoepitopes, a key regulator of the tumor immune microenvironment, and immunotherapeutic applications specific to this oncogenic fusion.

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来源期刊
EMBO Molecular Medicine
EMBO Molecular Medicine 医学-医学:研究与实验
CiteScore
17.70
自引率
0.90%
发文量
105
审稿时长
4-8 weeks
期刊介绍: EMBO Molecular Medicine is an open access journal in the field of experimental medicine, dedicated to science at the interface between clinical research and basic life sciences. In addition to human data, we welcome original studies performed in cells and/or animals provided they demonstrate human disease relevance. To enhance and better specify our commitment to precision medicine, we have expanded the scope of EMM and call for contributions in the following fields: Environmental health and medicine, in particular studies in the field of environmental medicine in its functional and mechanistic aspects (exposome studies, toxicology, biomarkers, modeling, and intervention). Clinical studies and case reports - Human clinical studies providing decisive clues how to control a given disease (epidemiological, pathophysiological, therapeutic, and vaccine studies). Case reports supporting hypothesis-driven research on the disease. Biomedical technologies - Studies that present innovative materials, tools, devices, and technologies with direct translational potential and applicability (imaging technologies, drug delivery systems, tissue engineering, and AI)
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