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. 2025 May;132(9):793-804.
doi: 10.1038/s41416-025-02981-y. Epub 2025 Mar 24.

Claudin18.2-positive gastric cancer-specific changes in neoadjuvant chemotherapy-driven immunosuppressive tumor microenvironment

Chikanori Tsutsumi  1 , Kenoki Ohuchida  2   3 , Yutaka Yamada  4 , Yuki Shimada  4 , Masaki Imamura  1 , Kiwa Son  1 , Yuki Mochida  1 , Naoki Katayama  1 , Chika Iwamoto  1 , Nobuhiro Torata  1 , Kohei Horioka  1 , Koji Shindo  1 , Yusuke Mizuuchi  1 , Naoki Ikenaga  1 , Kohei Nakata  1 , Hideya Onishi  5 , Yoshinao Oda  4 , Masafumi Nakamura  1
Affiliations

Claudin18.2-positive gastric cancer-specific changes in neoadjuvant chemotherapy-driven immunosuppressive tumor microenvironment

Chikanori Tsutsumi et al. Br J Cancer. 2025 May.

Abstract

Background: Claudin 18 isoform 2 (CLDN18.2) is a potential therapeutic target in gastric cancer (GC). However, combining chemotherapy with anti-CLDN18.2 antibodies has shown limited efficacy in CLDN18.2-positive GC, and chemotherapy-induced changes in the tumor microenvironment (TME) remain unclear.

Methods: This study analyzed 37 GC samples, including 11 CLDN18.2-positive cases, using single-cell RNA sequencing and multiplex immunofluorescence to assess chemotherapy-driven TME changes in CLDN18.2-positive GC.

Results: In chemotherapy-treated CLDN18.2-positive GC, cytotoxic natural killer (NK) cells displayed antibody-dependent cytotoxicity (ADCC)-related genes at lower levels than in untreated CLDN18.2-positive GC, while regulatory T cells (Tregs) and tumor-associated macrophages (TAMs) showed TGFB1 expression at higher levels. Additionally, NK cells, Tregs, and TAMs were more abundant in chemotherapy-treated than untreated CLDN18.2-positive GC. These chemotherapy-induced changes were absent in CLDN18.2-negative GC. Cell-cell interaction analysis identified unique interactions in chemotherapy-treated CLDN18.2-positive GC, including CCL5-CCR5 signaling between cytotoxic NK cells (Sender) and effector Tregs (Receptor) and TGFB1-TGFBR signaling between effector Tregs (Sender) and TAMs (Receptor). Cytotoxic NK cells expressed CCL5 at higher levels, CCR5-positive Tregs were more prevalent, and TAMs exhibited higher TGF-β receptor signature scores in chemotherapy-treated than untreated CLDN18.2-positive GC.

Conclusions: Our findings indicate that chemotherapy can drive immunosuppressive TME modifications specific to CLDN18.2-positive GC.

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Conflict of interest statement

Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: All methods in this study were performed in accordance with the relevant guidelines and regulations. Specimens were collected from patients who underwent gastrectomy at Kyushu University Hospital, with written informed consent obtained between 2019 and 2023. Ethics approval for this study was obtained from the Kyushu University Ethics Committee (approval numbers: 2023-79 and 22002-00).

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