FARSB stratifies prognosis and cold tumor microenvironment across different cancer types:an integrated single cell and bulk RNA sequencing analysis

ZHANG Ziran; TAN Jiale; YU Zihang; LIU Chengdong; WANG Jian; WU Dehua; BAI Xue

doi:10.12122/j.issn.1673-4254.2023.05.01

Abstract：Objective Immunotherapy has brought significant clinical benefits to a subset of patients,but has thus far been disappointing in the treatment of immunologically"cold"tumors.Existing biomarkers that can precisely identify these populations are insufficient.In this context,a potential cold tumor microenvironment(TME)marker FARSBwas investigated to reveal its impact on TME and patients'response to immunotherapy across pan-cancer.Methods The expression levels and mutational landscape of FARSB in pan-cancer were investigated.Kaplan-Meier and univariate Cox regression analyses were applied to analyze the prognostic significance of FARSB.Pathways affected by FARSBwere investigated by gene set enrichment and variation analysis.The relationship between FARSBexpression and immune infiltration was examined using the TIMER2 and R packages.Single-cell RNA sequencing(scRNA-seq)data of several cancer types from GSE72056,GSE131907,GSE132465,GSE125449 and PMID32561858 were analyzed to validate the impact of FARSBon the TME.The predictive effect of FARSBon immunotherapy efficacy was explored in 3 immune checkpoint inhibitors(ICIs)-treated cohorts(PMID32472114,GSE176307,and Riaz2017).Results FARSB expression was significantly higher in 25 tumor tissues than in normal tissues and was associated with poor prognosis in almost all tumor types.FARSBexpression exhibited a strong association with several DNA damage repair pathways and was significantly associated with TP53 mutation in lung adenocarcinoma(P<0.0001,OR=2.25).FARSB characterized a typical immune desert TME and correlated with impaired expression of chemokines and chemokines receptors.Large-scale scRNA-seq analysis confirmed the immunosuppressive role of FARSBand revealed that FARSBpotentially shapes the cold TME by impeding intercellular interactions.In 3 ICI-treated cohorts,FARSB demonstrated predictive value for immunotherapy.Conclusion This study provides a pan-cancer landscape of the FARSB gene by integrated single-cell and bulk DNA sequencing analysis and elucidates its biological function to promote DNA damage repair and construct the immune desert TME,suggesting the potential value of FARSBas a novel marker for stratifying patients with poor immunotherapeutic benefits and"cold"TME.