Cancer Research Institute, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-Gu, Seoul, 03080, Korea.
Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, 03080, Korea.
Cell Commun Signal. 2024 Oct 24;22(1):518. doi: 10.1186/s12964-024-01893-3.
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.
尽管曲妥珠单抗-德鲁替康（T-DXd）对 HER2 阳性胃癌（GC）的疗效推动了其临床应用，但调节其免疫调节作用的确切机制仍不清楚。在这项研究中，我们研究了 T-DXd 在 GC 细胞中的免疫相关作用机制。T-DXd 通过诱导 DNA 损伤和细胞凋亡，在不同 HER2 表达水平的 GC 细胞中均显示出强大的抗肿瘤作用。T-DXd 通过激活 DNA 损伤反应导致 PD-L1 表达增加。RNA-Seq 分析显示，T-DXd 调节免疫相关通路，导致与炎症和 IFN 信号相关的基因上调。重要的是，T-DXd 激活了 cGAS-STING 通路，在 HER2 阳性 GC 细胞中诱导 IFN-I 反应。此外，T-DXd 通过肿瘤细胞内在的 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作用。这些发现为 cGAS-STING 通路在 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联合用于 GC 治疗提供了强有力的理论依据。
