Claudin18.2-positive gastric cancer-specific changes in neoadjuvant chemotherapy-driven immunosuppressive tumor
Chikanori Tsutsumi1, Kenoki Ohuchida2,3, Yutaka Yamada4
1Department of Surgery and Oncology, Graduate School of Medical Sciences; Kyushu University, Fukuoka, Japan.
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.
Insights
Chemotherapy alters the tumor microenvironment in Claudin 18.2-positive gastric cancer, increasing immunosuppressive cells like Tregs and TAMs. These changes, including altered NK cell function, are specific to CLDN18.2-positive tumors.
Area of Science:
- Oncology
- Immunology
- Cancer Biology
Background:
- Claudin 18 isoform 2 (CLDN18.2) is a therapeutic target in gastric cancer (GC).
- Limited efficacy of combining chemotherapy with anti-CLDN18.2 antibodies in CLDN18.2-positive GC.
- Chemotherapy-induced tumor microenvironment (TME) changes in CLDN18.2-positive GC are not well understood.
Purpose of the Study:
- To investigate chemotherapy-driven TME modifications in CLDN18.2-positive GC.
- To assess the impact of chemotherapy on immune cell populations and their interactions within the TME.
Main Methods:
- Analysis of 37 GC samples (11 CLDN18.2-positive) using single-cell RNA sequencing and multiplex immunofluorescence.
- Assessment of chemotherapy-induced TME changes in CLDN18.2-positive GC.
Main Results:
- Chemotherapy treatment in CLDN18.2-positive GC led to decreased cytotoxic natural killer (NK) cell ADCC-related gene expression.
- Increased abundance and TGFB1 expression in regulatory T cells (Tregs) and tumor-associated macrophages (TAMs) post-chemotherapy.
- Chemotherapy-induced TME changes, including altered cell-cell signaling (CCL5-CCR5, TGFB1-TGFBR), were specific to CLDN18.2-positive GC.
Conclusions:
- Chemotherapy induces immunosuppressive TME modifications in CLDN18.2-positive GC.
- These findings highlight TME alterations as a potential mechanism limiting combination therapy efficacy.
More Related Videos
Related Concept Videos
02:17The Tumor Microenvironment
01:27Tumor Immunotherapy