Immunomodulatory effects of trastuzumab deruxtecan through the cGAS-STING pathway in gastric cancer cells.

IF 8.2 2区 生物学 Q1 CELL BIOLOGY
Kyoung-Seok Oh, Ah-Rong Nam, Ju-Hee Bang, Yoojin Jeong, Sea Young Choo, Hyo Jung Kim, Su In Lee, Jae-Min Kim, Jeesun Yoon, Tae-Yong Kim, Do-Youn Oh
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引用次数: 0

Abstract

Although the efficacy of trastuzumab deruxtecan (T-DXd) against HER2-positive gastric cancers (GCs) has driven its clinical application, the precise mechanisms governing its immunomodulatory role remain unclear. In this study, we examined the immune-related mechanisms of action of T-DXd in GC cells. T-DXd exhibited potent antitumor effects in GC cells across diverse HER2 expression levels by inducing DNA damage and apoptosis. Activation of the DNA damage response by T-DXd led to increased PD-L1 expression. RNA-Seq analysis revealed that T-DXd modulated immune-related pathways, resulting in the upregulation of genes associated with inflammation and IFN signaling. Importantly, T-DXd activated the cGAS-STING pathway, inducing an IFN-I response in HER2-positive GC cells. Furthermore, T-DXd activated dendritic cells via the cancer cell-intrinsic cGAS-STING-IFN axis and enhanced PBMC-mediated tumor cell killing by activating CD8+ T cells. These findings provide valuable insights into the role of the cytosolic DNA sensing pathway in the action of T-DXd and offer a compelling rationale for combining T-DXd with immune checkpoint blockade therapies in GC treatment.

曲妥珠单抗德鲁替康通过 cGAS-STING 通路对胃癌细胞产生免疫调节作用
尽管曲妥珠单抗德鲁司坦(T-DXd)对 HER2 阳性胃癌(GC)的疗效推动了其临床应用,但其免疫调节作用的确切机制仍不清楚。在这项研究中,我们考察了 T-DXd 在 GC 细胞中与免疫相关的作用机制。通过诱导 DNA 损伤和细胞凋亡,T-DXd 在不同 HER2 表达水平的 GC 细胞中表现出了强大的抗肿瘤作用。T-DXd激活DNA损伤反应导致PD-L1表达增加。RNA-Seq分析显示,T-DXd调节了免疫相关通路,导致炎症和IFN信号转导相关基因上调。重要的是,T-DXd 激活了 cGAS-STING 通路,诱导 HER2 阳性 GC 细胞产生 IFN-I 反应。此外,T-DXd 还通过癌细胞内在的 cGAS-STING-IFN 轴激活树突状细胞,并通过激活 CD8+ T 细胞增强 PBMC 介导的肿瘤细胞杀伤力。这些发现为了解细胞膜DNA感应途径在T-DXd作用中的作用提供了有价值的见解,并为将T-DXd与免疫检查点阻断疗法相结合治疗GC提供了令人信服的理由。
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来源期刊
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.
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