Zhang Ziran, Tan Jiale, Yu Zihang, Liu Chengdong, Wang Jian, Wu Dehua, Bai Xue
Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China.
Nan Fang Yi Ke Da Xue Xue Bao. 2023 May 20;43(5):667-679. doi: 10.12122/j.issn.1673-4254.2023.05.01.
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 was investigated to reveal its impact on TME and patients' response to immunotherapy across pan-cancer.
The expression levels and mutational landscape of in pan-cancer were investigated. Kaplan-Meier and univariate Cox regression analyses were applied to analyze the prognostic significance of . Pathways affected by were investigated by gene set enrichment and variation analysis. The relationship between 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 on the TME. The predictive effect of on immunotherapy efficacy was explored in 3 immune checkpoint inhibitors (ICIs)- treated cohorts (PMID32472114, GSE176307, and Riaz2017).
expression was significantly higher in 25 tumor tissues than in normal tissues and was associated with poor prognosis in almost all tumor types. expression exhibited a strong association with several DNA damage repair pathways and was significantly associated with mutation in lung adenocarcinoma ( < 0.0001, OR=2.25). 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 and revealed that potentially shapes the cold TME by impeding intercellular interactions. In 3 ICI-treated cohorts, demonstrated predictive value for immunotherapy.
This study provides a pan-cancer landscape of the 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 as a novel marker for stratifying patients with poor immunotherapeutic benefits and "cold" TME.
免疫疗法已给部分患者带来显著的临床益处，但迄今为止在免疫“冷”肿瘤的治疗中效果不佳。现有的能够精准识别这些人群的生物标志物并不充足。在此背景下，研究了一种潜在的冷肿瘤微环境（TME）标志物，以揭示其在泛癌中对肿瘤微环境及患者免疫治疗反应的影响。
研究了泛癌中该标志物的表达水平和突变图谱。应用Kaplan-Meier法和单变量Cox回归分析来分析该标志物的预后意义。通过基因集富集和变异分析研究受该标志物影响的信号通路。使用TIMER2和R软件包检查该标志物表达与免疫浸润之间的关系。分析了来自GSE72056、GSE131907、GSE132465、GSE125449和PMID32561858的几种癌症类型的单细胞RNA测序（scRNA-seq）数据，以验证该标志物对肿瘤微环境的影响。在3个接受免疫检查点抑制剂（ICI）治疗的队列（PMID32472114、GSE176307和Riaz2017）中探索该标志物对免疫治疗疗效的预测作用。
该标志物在25种肿瘤组织中的表达显著高于正常组织，且在几乎所有肿瘤类型中均与不良预后相关。该标志物的表达与多种DNA损伤修复信号通路密切相关，且在肺腺癌中与该标志物突变显著相关（P<0.0001, OR=2.25）。该标志物表征了一种典型的免疫荒漠肿瘤微环境，并与趋化因子和趋化因子受体的表达受损相关。大规模scRNA-seq分析证实了该标志物的免疫抑制作用，并揭示其可能通过阻碍细胞间相互作用塑造冷肿瘤微环境。在3个接受ICI治疗的队列中，该标志物对免疫治疗具有预测价值。
本研究通过整合单细胞和大量DNA测序分析，提供了该基因的泛癌图谱，并阐明了其促进DNA损伤修复和构建免疫荒漠肿瘤微环境的生物学功能，提示该标志物作为一种新型标志物，在对免疫治疗效果不佳和具有“冷”肿瘤微环境的患者进行分层方面具有潜在价值。
