Identification of cancer-associated fibroblast subpopulation and construction of an immunotherapy signature for gastric cancer.

BACKGROUNDCancer-associated fibroblasts (CAFs) are thought to contribute to malignant tumor progression. Although it has been reported that signatures based on CAFs-specific genes could be used to evaluate the prognosis of gastric cancer (GC), as a heterogeneous subgroup, the CAFs subpopulations and their characteristics in the GC microenvironment were still ambiguous. This study aimed to identify CAFs subgroups in GC and evaluate their prognostic and immunotherapy relevance.

METHODSWe utilized the Gene Expression Omnibus (GEO) database to acquire single-cell sequencing data of CAFs associated with GC, and The Cancer Genome Atlas (TCGA) database to obtain GC patient messenger RNA (mRNA) expression profiles. All CAFs were classified using unsupervised clustering based on the expression of 235 characteristic genes. The unsupervised clustering results indicated that the CAFs in the GC microenvironment were divided into four clusters. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed the intrinsic differences of these clusters and the CIBERSORT algorithm was used to perform immune cell infiltration analysis.

RESULTSCluster1, Cluster2 and Cluster4 were partly related to extracellular matrix production, while Cluster3 was mainly related to the TGF-β pathway. In addition, the CAF-related score based on Cluster3 (CRS3) could significantly distinguish the prognosis of patients. Moreover, patients with low CRS3 scores had a higher tumor mutation burden and higher levels of immune checkpoints (CTLA-4, LAG3, MAGE-A3, PD-1 and PD-L1), which might indicate a higher immunotherapy response.

CONCLUSIONSAll in all, our study revealed four heterogeneous subpopulations of CAFs in the GC microenvironment, and highlighted that Cluster3 was associated with prognosis and response to immunotherapy.