Li Jiarui, Tao Min, Liu Lian, Liu Chang, Ma Mingyang, Liu Dan, Zhang Panpan, Zhang Miao, Xue Ran, Gong Jifang, Zhang Cheng, Zhang Xiaotian, Shen Lin, Qi Changsong
Beijing Key Laboratory of Cell & Gene Therapy for Solid Tumor, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China.
Beijing Key Laboratory of Cell & Gene Therapy for Solid Tumor, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Early Drug Development Centre, Peking University Cancer Hospital & Institute, Beijing, China.
Br J Cancer. 2025 Apr 17. doi: 10.1038/s41416-025-03015-3.
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.
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.
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.
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.
NCT03874897.
Claudin18.2（CLDN18.2）特异性嵌合抗原受体（CAR）-T细胞疗法对晚期胃癌（GC）治疗具有前景，但疗效存在差异。本研究调查中性粒细胞与淋巴细胞比值（NLR）在CAR-T细胞治疗中的预后价值，并阐明治疗耐药的分子机制。
分析接受CLDN18.2特异性CAR-T细胞治疗的GC患者。观察指标包括客观缓解率（ORR）、疾病控制率（DCR）、无进展生存期（PFS）和总生存期（OS）。生存分析采用Kaplan-Meier法、对数秩检验和Cox回归。对外周血样本进行单细胞RNA测序，以研究促肿瘤循环中性粒细胞的机制。
NLR升高与较低的ORR（34.2%对55.9%，P<0.001）、较短的中位PFS（3.6个月对8.0个月，P<0.001）和OS（5.6个月对13.8个月，P<0.001）显著相关。单细胞测序确定了一个与疾病进展相关的循环中性粒细胞亚群（NE-3）。NE-3表达促肿瘤因子（MMP-9），并在IL-17信号通路中富集。中性粒细胞与T细胞之间的细胞相互作用在疾病进展（PD）组比部分缓解（PR）组更显著。
本研究强调NLR是接受CLDN18.2特异性CAR-T细胞治疗的晚期GC患者的重要预后因素，并为中性粒细胞介导的治疗耐药提供了见解。需要进一步验证和探索减轻中性粒细胞诱导的免疫抑制的策略。
NCT03874897
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