POSTN Secretion by Extracellular Matrix Cancer-Associated Fibroblasts (eCAFs) Correlates with Poor ICB Response via Macrophage Chemotaxis Activation of Akt Signaling Pathway in Gastric Cancer

作者：Tingting You, Hui Tang, Wenjing Wu, Jingxi Gao, Xuechun Li, Ningning Li, Xiuxiu Xu, Jiazhang Xing, Hui Ge, Yi Xiao, Junchao Guo, Bin Wu, Xiaoyi Li, Liangrui Zhou, Lin Zhao, Chunmei Bai, Qin Han, Zhao Sun, Robert Chunhua Zhao · 发表于：Aging and Disease · 年份：2023 · DOI：10.14336/ad.2023.0503 · 被引用次数：37 · 研究领域：Cancer Immunotherapy and Biomarkers、Immune cells in cancer、Cancer Cells and Metastasis

Immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment, but its clinical benefit is limited in advanced gastric cancer (GC). Cancer-associated fibroblasts (CAFs) have been reported to be associated with ICB resistance, but the underlying mechanism has not been fully elucidated. Our previous single-cell RNA-seq analysis of GC revealed that POSTN+FAP+ extracellular matrix CAFs (eCAFs) communicate with macrophages. Here, we evaluated the correlation between eCAFs and ICB response in TCGA-STAD and real-world cohorts. Immune infiltration analysis and correlation analysis were performed to assess the relationship between eCAFs and macrophages. We first confirmed a negative correlation between the abundance of eCAFs and the overall response rate (ORR) to anti-PD-1 treatment in TCGA-STAD and real-world GC cohorts. Overexpression of POSTN in CAFs enhanced macrophage chemotaxis, while POSTN interference showed the opposite effect in vitro and in vivo. Furthermore, the cell density of POSTN+ CAFs was positively correlated with the infiltration level of CD163+ macrophages in GC patient tissues. The results demonstrated that POSTN secreted by CAFs enhances macrophage chemotaxis by activating the Akt signaling pathway in macrophages. Additionally, we found that POSTN+FAP+ eCAFs may exist in multiple solid tumors and are associated with ICB resistance. eCAFs promote macrophage chemotaxis through the secretion of POSTN, thereby leading to ICB resistance. High expression...