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Background <p>Claudin18.2 (CLDN18.2)-specific chimeric antigen receptor (CAR)-T cell treatment holds promise for advanced&#xa0;gastric cancer (GC) but has variable efficacy. This study investigates the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) in CAR-T cell&#xa0;treatment and elucidates the molecular mechanisms of treatment resistance.</p> Methods <p>GC patients treated with CLDN18.2-specific CAR-T cell&#xa0;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.</p> Results <p>Elevated NLR was significantly associated with lower ORR (34.2% vs. 55.9%, <i>P</i> &lt; 0.001), shorter median PFS (3.6 vs. 8.0 months, <i>P</i> &lt; 0.001), and OS (5.6 vs. 13.8 months, <i>P</i> &lt; 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.</p> Conclusions <p>This study highlights NLR as a significant prognostic factor in advanced GC patients receiving CLDN18.2-specific CAR-T cell&#xa0;treatment and provides insights into neutrophil-mediated treatment resistance. Further validation and exploration of strategies to mitigate neutrophil-induced immunosuppression are needed.</p> Trial Registration <p>NCT03874897.</p>

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

  • 期刊论文

  • 发表日期：

    2025年4月17日

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  • Jiarui Li,
  • Min Tao,
  • Lian Liu,
  • Chang Liu,
  • Mingyang Ma,
  • Dan Liu,
  • Panpan Zhang,
  • Miao Zhang,
  • Ran Xue,
  • Jifang Gong,
  • Cheng Zhang,
  • Xiaotian Zhang,
  • Lin Shen,
  • Changsong Qi

摘要

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.