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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>Our findings indicate that chemotherapy can drive immunosuppressive TME modifications specific to CLDN18.2-positive GC.</p>

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

  • 期刊论文

  • 发表日期：

    2025年3月24日

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

摘要

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.