Jian Mi, Yang Zhensong, Tang Yutao, Jiang Fangjie, Cai Li, Liu Aina, Hu Jinchen, Wang Xixun, Liu Shuguang, Zhao Dawei, Li Miaomiao, Chen Hongbing, Zhang Menglai, Yao Zengwu, Jia Rongbao, Chen Ruyue, Jiang Lixin, Zhang Yifei, Song Xicheng
Department of Gastrointestinal Surgery, Yantai Yuhuangding Hospital Affiliated to Medical College of Qingdao University, Yantai 264000, Shandong, China.
Department of Endocrinology, Yantai Yuhuangding Hospital Affiliated to Medical College of Qingdao University, Yantai 264000, Shandong, China.
APL Bioeng. 2025 Aug 28;9(3):036115. doi: 10.1063/5.0250475. eCollection 2025 Sep.
The achievement of pathological complete response (pCR) with neoadjuvant therapy can significantly improve prognosis in patients with gastric cancer (GC). GC tissues demonstrating pCR after immunotherapy exhibited increased stiffness and proliferation of fibroblasts within the stroma. Specific subpopulation cancer-associated fibroblasts (CAFs) may serve as potential markers for predicting the efficacy of immunotherapy. We screened CAFs-related genes as candidate predictors for immunotherapy using the TCGA-STAD, PRJEB25780, GSE27342, and GSE54129 databases. Tissue specimen from GC patients enrolled in the clinical trial (NCT04208347) was used to evaluate its clinical significance. Single-cell RNA sequencing (scRNA-seq) data were obtained from GSE163558, GSE183904, and GSE184198 datasets and analyzed through Seurat v3 R software and iTALK. GC patient-derived organoids (GC-PDOs) modeling verified the effect of CAFs subpopulations on immunotherapeutic response . Podoplanin (PDPN) has been identified as a candidate marker related to CAFs for predicting the efficacy of immunotherapy. Western blot analysis indicated that lower PDPN expression was observed in GC samples with pCR. Functional and pathway enrichment analysis indicated PDPN was associated with numerous malignancy-related pathways in gastric cancer. Using the iTALK algorithm, scRNA-seq datasets further verified the interaction between a subpopulation of PDPN+ CAFs and immune cells. The results of multiple immunohistochemistry/immunofluorescence suggested a negative correlation between PDPN+ CAFs and pCR to anti-PD-1 treatment ( < 0.01). Notably, using the GC-PDO model, we determined that PDPN + CAFs hinder the activation, thereby reducing immune response in GC patients. PDPN+ CAFs subpopulation has a potential correlation with the efficacy of immunotherapy for GC patients.
新辅助治疗实现病理完全缓解（pCR）可显著改善胃癌（GC）患者的预后。免疫治疗后显示pCR的GC组织表现出基质内成纤维细胞硬度增加和增殖。特定亚群的癌症相关成纤维细胞（CAFs）可能作为预测免疫治疗疗效的潜在标志物。我们使用TCGA-STAD、PRJEB25780、GSE27342和GSE54129数据库筛选与CAFs相关的基因作为免疫治疗的候选预测指标。来自参与临床试验（NCT04208347）的GC患者的组织标本用于评估其临床意义。单细胞RNA测序（scRNA-seq）数据来自GSE163558、GSE183904和GSE184198数据集，并通过Seurat v3 R软件和iTALK进行分析。GC患者来源的类器官（GC-PDOs）模型验证了CAFs亚群对免疫治疗反应的影响。血小板内皮细胞黏附分子（PDPN）已被确定为与CAFs相关的预测免疫治疗疗效的候选标志物。蛋白质免疫印迹分析表明，在达到pCR的GC样本中观察到较低的PDPN表达。功能和通路富集分析表明，PDPN与胃癌中许多恶性肿瘤相关通路有关。使用iTALK算法，scRNA-seq数据集进一步验证了PDPN+ CAFs亚群与免疫细胞之间的相互作用。多重免疫组织化学/免疫荧光结果表明，PDPN+ CAFs与抗PD-1治疗的pCR之间呈负相关（<0.01）。值得注意的是，使用GC-PDO模型，我们确定PDPN + CAFs会阻碍激活，从而降低GC患者的免疫反应。PDPN+ CAFs亚群与GC患者免疫治疗疗效具有潜在相关性。
