Department of Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Peking Union Medical College Hospital, Center of Excellence in Tissue Engineering Chinese Academy of Medical Sciences, Beijing Key Laboratory, Beijing, China.
Aging Dis. 2023 Dec 1;14(6):2177-2192. doi: 10.14336/AD.2023.0503.
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 of POSTN is likely to predict a poor response to ICB. POSTN downregulation may be considered as a candidate therapeutic strategy to improve ICB efficacy.
免疫检查点阻断 (ICB) 治疗已经彻底改变了癌症治疗，但在晚期胃癌 (GC) 中，其临床获益有限。已经有报道称癌症相关成纤维细胞 (CAFs) 与 ICB 耐药有关，但潜在机制尚未完全阐明。我们之前对 GC 的单细胞 RNA-seq 分析表明，POSTN+FAP+细胞外基质 CAFs (eCAFs) 与巨噬细胞相互交流。在这里，我们在 TCGA-STAD 和真实世界队列中评估了 eCAFs 与 ICB 反应之间的相关性。进行免疫浸润分析和相关性分析，以评估 eCAFs 与巨噬细胞之间的关系。我们首先在 TCGA-STAD 和真实世界 GC 队列中证实了 eCAFs 的丰度与抗 PD-1 治疗的总体反应率 (ORR) 之间存在负相关。CAFs 中 POSTN 的过表达增强了巨噬细胞的趋化性，而 POSTN 干扰则在体外和体内表现出相反的效果。此外，GC 患者组织中 POSTN+CAFs 的细胞密度与 CD163+巨噬细胞的浸润水平呈正相关。结果表明，CAFs 分泌的 POSTN 通过激活巨噬细胞中的 Akt 信号通路增强了巨噬细胞的趋化性。此外，我们发现 POSTN+FAP+eCAFs 可能存在于多种实体瘤中，并与 ICB 耐药有关。eCAFs 通过 POSTN 的分泌促进巨噬细胞趋化，从而导致 ICB 耐药。POSTN 的高表达可能预示着对 ICB 的反应不佳。下调 POSTN 可能被认为是提高 ICB 疗效的候选治疗策略。
