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Cellular and Molecular Biology

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

British Journal of Cancer volume 132, pages 793–804 (2025)Cite this article

Subjects

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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Fig. 1: ADCC-related gene expression of NK cells in CLDN18.2-positive GC treated with chemotherapy.
Fig. 2: Role of Tregs in CLDN18.2-positive gastric cancer treated with chemotherapy.
Fig. 3: Impact of TAMs in CLDN18.2-positive gastric cancer treated with chemotherapy.
Fig. 4: Association between NK cells and immunosuppressive cells in CLDN18.2-positive GC treated with chemotherapy.
Fig. 5: Cell-cell interactions between NK cells and immunosuppressive cells in CLDN18.2-positive gastric cancer treated with chemotherapy.
Fig. 6: Spatial distribution of immunosuppressive cells in CLDN18.2-positive gastric cancer treated with chemotherapy.

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Data availability

The scRNA-seq data used in this study are available in the GEO database under accession code GSE268238. One case was excluded due to the absence of residual cancer cells in the resected specimen. Additional data, including code information, are available within the article, its supplementary information, or upon request from the authors.

Code availability

The scRNA-seq data used in this study are available in the GEO database under accession code GSE268238. One case was excluded due to the absence of residual cancer cells in the resected specimen. Additional data, including code information, are available within the article, its supplementary information, or upon request from the authors.

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Acknowledgements

We thank E. Manabe and S. Sadatomi of Kyushu University for their expert technical assistance.

Funding

This study was funded by JSPS KAKENHI (Grant Number JP22H00480, JP23K27461, JP23K08175, JP24K11743, and JP24K11849) and JSPS Research Fellow PD (JP23KJ1698).

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Authors and Affiliations

  1. Department of Surgery and Oncology, Graduate School of Medical Sciences; Kyushu University, Fukuoka, Japan

    Chikanori Tsutsumi, Kenoki Ohuchida, Masaki Imamura, Kiwa Son, Yuki Mochida, Naoki Katayama, Chika Iwamoto, Nobuhiro Torata, Kohei Horioka, Koji Shindo, Yusuke Mizuuchi, Naoki Ikenaga, Kohei Nakata & Masafumi Nakamura

  2. Department of Advanced Medical Initiatives, Graduate School of Medical Sciences; Kyushu University, Fukuoka, Japan

    Kenoki Ohuchida

  3. Department of Anatomic Pathology, Graduate School of Medical Sciences; Kyushu University, Fukuoka, Japan

    Yutaka Yamada, Yuki Shimada & Yoshinao Oda

  4. Pancreatobiliary Surgery / Kidney & Pancreas Transplantation, Kyushu University Hospital, Fukuoka, Japan

    Hideya Onishi

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  1. Chikanori Tsutsumi
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Contributions

CT designed the experimental approach, performed the experimental work, analyzed data, coordinated projects, and wrote the manuscript. KO designed the experimental approach, analyzed data, wrote the manuscript, coordinated projects, and contributed to data interpretation and discussion. CT, MI, KS, YM and NT performed the experimental work. MI, KS, YM, CI, NK, YM, NI, KN and HO contributed to data interpretation and discussion. KO, KH and KS provided and prepared human samples. Immunohistochemistry was analyzed by CT, YY, YS and YO. MN coordinated projects, wrote the manuscript, and contributed to data interpretation and discussion.

Corresponding author

Correspondence to Kenoki Ohuchida.

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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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Tsutsumi, C., Ohuchida, K., Yamada, Y. et al. Claudin18.2-positive gastric cancer-specific changes in neoadjuvant chemotherapy-driven immunosuppressive tumor microenvironment. Br J Cancer 132, 793–804 (2025). https://doi.org/10.1038/s41416-025-02981-y

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