Zhou Chenfei, Guo Liting, Cai Qu, Xi Wenqi, Yuan Fei, Zhang Huan, Yan Chao, Huang Lei, Zhu Zhenggang, Zhang Jun
Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Oncology, Wuxi Branch of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Wuxi, China.
Front Mol Biosci. 2023 Jun 1;10:1081762. doi: 10.3389/fmolb.2023.1081762. eCollection 2023.
To analyze the correlation between the neutrophil-to-lymphocyte ratio (NLR) and prognosis of advanced gastric cancer (AGC) patients treated by PD-1 antibody-based therapy and to delineate molecular characteristics of circulating neutrophils by single-cell RNA sequencing (scRNA-seq). The clinicopathological information of 45 AGC patients receiving PD-1 antibody-based regimens at the Department of Oncology, Ruijin Hospital, was reviewed. Treatment outcomes including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were recorded. The correlation between NLR and efficacy of PD-1 antibody-based treatment was analyzed. Single-cell RNA sequencing (scRNA-seq) analysis was performed based on multisite biopsy samples from two AGC patients to explore the molecular characteristics of circulating neutrophils and their pro-tumor mechanisms. Tissue samples from 88 gastric cancer patients who underwent radial gastrectomy were collected for immunochemistry staining. A high posttreatment NLR was associated with poor outcomes of AGC patients receiving PD-1 antibody-based regimens. scRNA-seq analysis showed that an increased number of circulating neutrophils were found in peripheral blood samples after treatment in which neutrophil cluster 1 (NE-1) was the major subcluster. NE-1 was featured with a neutrophil activation phenotype with the high expression of , , , , and NE-1 displayed an intermediate state in pseudotime trajectory analysis with gene function enrichment found in neutrophil activation, leukocyte chemotaxis, and negative regulation of MAP kinase activity. Cellular interaction analysis showed that the chemokine signaling pathway is the major interactional pathway of NE-1 between subclusters of malignant epithelial cells (EP-4) and M2 macrophages (M2-1 and M2-2). In turn, the MAPK signaling pathway and Jak-STAT signaling pathway of EP-4, including IL1B/IL1RAP, OSM/OSMR, and TGFB1/TGFBR2 axes, were identified as interacting pathways between EP-4 and NE-1. The high expression of OSMR in tumor cells was closely correlated with lymph node metastasis of gastric cancer. The posttreatment NLR could be a poor prognostic marker of AGC patients treated with immune checkpoint inhibitors (ICIs). Subclusters of circulating neutrophils activated by tumor cells and M2 macrophages could participate in gastric cancer progression through signaling interactions with tumor cells.
分析接受基于PD-1抗体治疗的晚期胃癌（AGC）患者中性粒细胞与淋巴细胞比值（NLR）与预后的相关性，并通过单细胞RNA测序（scRNA-seq）描绘循环中性粒细胞的分子特征。回顾了瑞金医院肿瘤科45例接受基于PD-1抗体方案治疗的AGC患者的临床病理信息。记录治疗结果，包括客观缓解率（ORR）、无进展生存期（PFS）和总生存期（OS）。分析NLR与基于PD-1抗体治疗疗效之间的相关性。基于两名AGC患者的多部位活检样本进行单细胞RNA测序（scRNA-seq）分析，以探索循环中性粒细胞的分子特征及其促肿瘤机制。收集88例行根治性胃切除术的胃癌患者的组织样本进行免疫化学染色。治疗后高NLR与接受基于PD-1抗体方案治疗的AGC患者的不良预后相关。scRNA-seq分析显示，治疗后外周血样本中循环中性粒细胞数量增加，其中中性粒细胞簇1（NE-1）是主要亚簇。NE-1具有中性粒细胞活化表型，高表达 、 、 、 和 。在伪时间轨迹分析中，NE-1显示出中间状态，基因功能富集于中性粒细胞活化、白细胞趋化和丝裂原活化蛋白激酶活性的负调控。细胞相互作用分析表明，趋化因子信号通路是NE-1在恶性上皮细胞（EP-4）和M2巨噬细胞（M2-1和M2-2）亚簇之间的主要相互作用途径。反过来，EP-4的丝裂原活化蛋白激酶信号通路和Jak-STAT信号通路，包括IL1B/IL1RAP、OSM/OSMR和TGFB1/TGFBR2轴，被确定为EP-4与NE-1之间的相互作用途径。肿瘤细胞中OSMR的高表达与胃癌的淋巴结转移密切相关。治疗后NLR可能是接受免疫检查点抑制剂（ICI）治疗的AGC患者预后不良的标志物。被肿瘤细胞和M2巨噬细胞激活的循环中性粒细胞亚簇可通过与肿瘤细胞的信号相互作用参与胃癌进展。
