The Tumor Immune Microenvironment and Therapeutic Efficacy of Trastuzumab Deruxtecan in Gastric Cancer

作者：Shigehiro Koganemaru, Shohei Koyama, Fumitaka Suto, Makito Koga, Koichiro Inaki, Yusuke Kuwahara, Takeo Arita, Tsuyoshi Hirata, Hiroki Goto, Naoya Wada, Maki Kobayashi, Tomoko Shibutani, Tohru Okabayashi, Kenji Nakamaru, Akihito Kawazoe, Yosuke Togashi, Hiroyoshi Nishikawa, Kohei Shitara · 发表于：Cancer Research Communications · 年份：2024 · DOI：10.1158/2767-9764.crc-24-0302 · 被引用次数：9 · 研究领域：HER2/EGFR in Cancer Research、Gastric Cancer Management and Outcomes、Cancer Cells and Metastasis

ABSTRACT: Trastuzumab deruxtecan (T-DXd), an anti-HER2 antibody–drug conjugate with a topoisomerase I inhibitor connected by a cleavable linker, has been approved for patients with HER2-positive gastric or gastroesophageal junction tumors. This biomarker study assessed HER2 expression and immune cell infiltration in relation to the therapeutic response to T-DXd. This retrospective analysis included samples from patients treated with T-DXd in three clinical trials. We performed RNA sequencing and multiplex IHC on archival tumor samples obtained at baseline, during treatment, and after treatment. Flow cytometry was performed on tumor-infiltrating immune cells freshly isolated from tumor tissues. Samples from 28 patients were included in this study. ERBB2 mRNA levels and CD20+ cell infiltration in tumors were significantly higher at baseline in responders than in nonresponders. Patients were classified into three biological groups based on their baseline tumor/stroma-infiltrating immune cell densities. Two groups reported similar response rates, but a trend was observed toward a shorter progression-free survival in the group with more immunosuppressive regulatory T cells and PD-L1 expression at baseline. T-DXd treatment tended to increase the levels of tumor-infiltrating CD8+ T cells and PD1+CD8+ T cells, particularly in responders. Gene expression signatures of CTL and Th cells increased during treatment, whereas signatures related to hypoxia, MYC targets, collagen formation, a...