文章：

紫杉叶素通过下调与免疫逃逸因子具有新颖且显著关联的基因抑制非小细胞肺癌生长

Taxifolin Inhibits the Growth of Non-Small-Cell Lung Cancer via Downregulating Genes Displaying Novel and Robust Associations with Immune Evasion Factors

原文发布日期：30 September 2023

DOI: 10.3390/cancers15194818

类型: Article

开放获取: 是

英文摘要：

Using an LL2 cell-based syngeneic mouse LC model, taxifolin suppressed allografts along with the appearance of 578 differentially expressed genes (DEGs). These DEGs were associated with enhancement of processes related to the extracellular matrix and lymphocyte chemotaxis as well as the reduction in pathways relevant to cell proliferation. From these DEGs, we formulated 12-gene (TxflSig) and 7-gene (TxflSig1) panels; both predicted response to ICB (immune checkpoint blockade) therapy more effectively in non-small-cell lung cancer (NSCLC) than numerous well-established ICB biomarkers, including PD-L1. In both panels, the mouse counterparts ofITGAL,ITGAX, andTMEM119genes were downregulated by taxifolin. They were strongly associated with immune suppression in LC, evidenced by their robust correlations with the major immunosuppressive cell types (MDSC, Treg, and macrophage) and multiple immune checkpoints in NSCLC and across multiple human cancer types. ITGAL, ITGAX, and IIT (ITGAL-ITGAX-TMEM119) effectively predicted NSCLC’s response to ICB therapy; IIT stratified the mortality risk of NSCLC. The stromal expressions of ITGAL and ITGAX, together with tumor expression of TMEM119 in NSCLC, were demonstrated. Collectively, we report multiple novel ICB biomarkers—TxflSig, TxflSig1, IIT, ITGAL, and ITGAX—and taxifolin-derived attenuation of immunosuppressive activities in NSCLC, suggesting the inclusion of taxifolin in ICB therapies for NSCLC.

摘要翻译： 

利用基于LL2细胞的同基因小鼠肺癌模型，花旗松素抑制了同种异体移植瘤的生长，并伴随578个差异表达基因的出现。这些差异表达基因与细胞外基质相关过程及淋巴细胞趋化作用的增强有关，同时与细胞增殖相关通路的下调相关联。基于这些差异表达基因，我们构建了12基因（TxflSig）和7基因（TxflSig1）特征集；两者在预测非小细胞肺癌对免疫检查点阻断疗法的反应方面，均优于包括PD-L1在内的多种已确立的生物标志物。在这两个特征集中，ITGAL、ITGAX和TMEM119基因的小鼠同源基因均被花旗松素下调。这些基因与肺癌中的免疫抑制密切相关，其与非小细胞肺癌及多种人类癌症类型中主要免疫抑制细胞类型（髓源性抑制细胞、调节性T细胞和巨噬细胞）以及多个免疫检查点的强相关性证实了这一点。ITGAL、ITGAX及IIT（ITGAL-ITGAX-TMEM119）组合能有效预测非小细胞肺癌对免疫检查点阻断疗法的反应；IIT可对非小细胞肺癌的死亡风险进行分层。研究证实了ITGAL和ITGAX在非小细胞肺癌间质中的表达，以及TMEM119在肿瘤中的表达。综上所述，我们报告了多个新型免疫检查点阻断生物标志物——TxflSig、TxflSig1、IIT、ITGAL和ITGAX，以及花旗松素对非小细胞肺癌免疫抑制活性的减弱作用，这提示可将花旗松素纳入非小细胞肺癌的免疫检查点阻断治疗中。

原文链接：

Taxifolin Inhibits the Growth of Non-Small-Cell Lung Cancer via Downregulating Genes Displaying Novel and Robust Associations with Immune Evasion Factors