Cell Communication and Signaling (Oct 2024)

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

  • 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

DOI
https://doi.org/10.1186/s12964-024-01893-3
Journal volume & issue
Vol. 22, no. 1
pp. 1 – 16

Abstract

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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.

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