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.

中文翻译：

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针对胃癌中致癌融合基因 CLDN18-ARHGAP 的免疫疗法。


CLDN18-ARHGAP融合基因是在胃癌中新发现的致癌驱动基因。我中心9%（8/87）的胃癌患者中检出该基因。产生了一种特异性靶向CLDN18-ARHGAP融合基因的免疫原性肽来诱导新抗原反应性T细胞，在体外共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，CLDN18-ARHGAP 融合基因还被发现通过诱导富含调节性 T (Treg) 细胞的微环境来促进免疫抑制。从机制上讲，具有 CLDN18-ARHGAP 融合的胃癌细胞激活 PI3K/AKT-mTOR-FAS 信号传导，从而增强胃癌细胞游离脂肪酸的产生，从而有利于 Treg 细胞的存活。此外，PI3K抑制可以有效逆转Treg细胞的上调，从而增强体外新抗原反应性T细胞的抗肿瘤细胞毒性，并减少异种移植胃癌模型中的肿瘤生长。我们的研究确定 CLDN18-ARHGAP 融合基因是免疫原性新表位的关键来源，是肿瘤免疫微环境的关键调节剂，以及针对这种致癌融合的免疫治疗应用。