PDPN+ cancer-associated fibroblasts correlate with the neoadjuvant immunotherapy response in gastric cancer
Year: 2025
Type: article
Abstract: 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 in vitro. 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 (p < 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.
Source: APL Bioengineering
DOI: 10.1063/5.0250475
Authors: Mi Jian, Zhensong Yang, Yutao Tang, Fangjie Jiang, Li Cai, Aina Liu, Jinchen Hu, Xixun Wang, Shuguang Liu, Dawei Zhao, Miaomiao Li, Hongbing Chen, Menglai Zhang, Zengwu Yao, Rongbao Jia, Ruyue Chen, Lixin Jiang, Yifei Zhang, Xicheng Song
Institutions: Qingdao University, Yuhuangding Hospital
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,200
Funders: National Natural Science Foundation of China, Shanghai Jiao Tong University, Natural Science Foundation of Shandong Province, Taishan Scholar Project of Shandong Province, Yantai Science and Technology Bureau, Ruijin Hospital, Wu Jieping Medical Foundation, Key Technology Research and Development Program of Shandong
OpenAlex ID: W4413789287