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Clinical Trial
. 2025 Jun;132(12):1167-1176.
doi: 10.1038/s41416-025-03015-3. Epub 2025 Apr 17.

Peripheral blood neutrophils contribute to Claudin18.2-specific CAR-T cell treatment resistance in advanced gastric cancer

Jiarui Li #  1 , Min Tao #  1 , Lian Liu #  1 , Chang Liu  2 , Mingyang Ma  1 , Dan Liu  2 , Panpan Zhang  2 , Miao Zhang  2 , Ran Xue  2 , Jifang Gong  3 , Cheng Zhang  3 , Xiaotian Zhang  4 , Lin Shen  5 , Changsong Qi  6
Affiliations
Clinical Trial

Peripheral blood neutrophils contribute to Claudin18.2-specific CAR-T cell treatment resistance in advanced gastric cancer

Jiarui Li et al. Br J Cancer. 2025 Jun.

Abstract

Background: Claudin18.2 (CLDN18.2)-specific chimeric antigen receptor (CAR)-T cell treatment holds promise for advanced gastric cancer (GC) but has variable efficacy. This study investigates the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) in CAR-T cell treatment and elucidates the molecular mechanisms of treatment resistance.

Methods: GC patients treated with CLDN18.2-specific CAR-T cell treatment were analyzed. Outcomes included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Survival analyses utilized Kaplan-Meier methods, log-rank tests, and Cox regression. Single-cell RNA sequencing was performed on peripheral blood samples to investigate the mechanisms of pro-tumor circulating neutrophils.

Results: Elevated NLR was significantly associated with lower ORR (34.2% vs. 55.9%, P < 0.001), shorter median PFS (3.6 vs. 8.0 months, P < 0.001), and OS (5.6 vs. 13.8 months, P < 0.001). Single-cell sequencing identified a circulating neutrophil subcluster (NE-3) linked to disease progression. NE-3 expressed pro-tumoral factors (MMP-9), and was enriched in the IL-17 signaling pathway. The cellular interactions between neutrophils and T cells were more prominent in progression disease (PD) group than in partial response (PR) group.

Conclusions: This study highlights NLR as a significant prognostic factor in advanced GC patients receiving CLDN18.2-specific CAR-T cell treatment and provides insights into neutrophil-mediated treatment resistance. Further validation and exploration of strategies to mitigate neutrophil-induced immunosuppression are needed.

Trial registration: NCT03874897.

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Conflict of interest statement

Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: The study was approved by the Ethics Committee of Peking University Cancer Hospital (2018YJZ75). The study was performed in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. All patients provided written informed consent before participation in this trial.

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