南方医科大学学报

南方医科大学学报 ›› 2023, Vol. 43 ›› Issue (5): 667-679.doi: 10.12122/j.issn.1673-4254.2023.05.01

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FARSB对泛肿瘤的预后和冷肿瘤微环境的分层作用：基于整合单细胞和大块组织的DNA测序

张自然，谭家乐，于子航，刘承栋，王 剑，吴德华，白 雪   

  1. 南方医科大学南方医院，广东 广州 510515；南方医科大学第一临床医学院，广东 广州 510515
  • 出版日期:2023-05-20 发布日期:2023-06-12

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   

  1. Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
  • Online:2023-05-20 Published:2023-06-12

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摘要： 目的 研究一个潜在的冷肿瘤微环境标志物——FARSB基因在泛癌中对肿瘤微环境以及患者对免疫治疗的反应的影响。方法 使用生物信息学方法研究FARSB在泛癌组织中的表达水平及突变情况。采用Kaplan-Meier和单因素Cox回归分析FARSB的预后意义。通过基因集富集和变异分析，研究受FARSB影响的信号转导途径。用TIMER2数据库和R软件包分析FARSB表达与免疫浸润的关系。分析队列GSE72056，GSE131907，GSE132465，GSE125449和PMID32561858的单细胞RNA测序数据，以验证FARSB对肿瘤微环境的影响。在3个接受免疫检查点抑制剂治疗的队列中（PMID32472114、GSE176307和Riaz2017）中，探讨FARSB对免疫治疗疗效的预测作用。结果 FARSB在25种肿瘤组织中的表达明显高于正常组织，并且几乎在所有肿瘤类型中都与不良预后有关。FARSB的表达与多种DNA损伤修复途径密切相关，与肺腺癌组织中基因TP53的突变显著相关（P<0.0001，OR=2.25）。FARSB表征了典型的免疫沙漠型肿瘤微环境，且与趋化因子及趋化因子受体表达受抑制有关。大规模的单细胞RNA测序分析证实了FARSB的免疫抑制作用，并揭示了FARSB通过阻碍细胞间相互作用而潜在地塑造冷肿瘤微环境。在3个接受免疫检查点抑制剂治疗的队列中，FARSB对免疫治疗效果显示出良好的预测价值。结论 本研究通过整合单细胞和大块组织RNA测序分析，提供了FARSB基因的泛癌图谱，阐明了其促进DNA损伤修复和构建免疫沙漠型肿瘤微环境的生物学功能。FARSB基因为免疫治疗效果差的人群和冷肿瘤微环境人群的分层提供了一个新的生物标记物。

关键词: FARSB；免疫治疗；泛癌；DNA损伤修复；肿瘤微环境

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 FARSB was 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 FARSB were investigated by gene set enrichment and variation analysis. The relationship between FARSB expression 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 FARSB on the TME. The predictive effect of FARSB on 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. FARSB expression 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 FARSB and revealed that FARSB potentially 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 FARSB as a novel marker for stratifying patients with poor immunotherapeutic benefits and "cold" TME.

Key words: FARSB; immunotherapy; pan-cancer; DNAdamage repair; tumor microenvironment