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Abstract：
Immune checkpoint blockade (ICB) therapy has resulted in improved overall survival in kidney renal clear cell carcinoma (KIRC), but most treated patients fail to show durable clinical responses. Lymphocyte activation gene-3 (LAG3) is a novel inhibitory immune checkpoint, but its expression pattern, prognostic value, and immunological role in KIRC remain unknown. In this study, we utilized TCGA_KIRC RNA-sequencing data to analyze the relationship between LAG3 expression and clinical features. The single-cell sequencing data and tissue immunofluorescence are employed to investigate the subcellular localization of LAG3 in KIRC. Kaplan-Meier plotter, TIMER, and TISIDB were used to assess the association between LAG3 expression and prognosis, as well as its correlation with immune-related components. We constructed the LAG3 interaction network by using STRING, GeneMANIA, BioGRID, and HitPredict databases. We found that LAG3 is upregulated and correlates with poor prognostic phenotype in KIRC. LAG3 is predominantly expressed on exhausted CD8+ T cells and shows strong co-expression with PDCD1 in KIRC. Moreover, our findings indicated that LAG3 not only inhibits T cell activation but also potentially regulates cell adhesion in KIRC. In conclusion, our study implies that LAG3 can serve as a potential prognostic biomarker for KIRC. Furthermore, blocking both LAG3 and PDCD1 may alleviate resistance to anti-PDCD1 therapy, providing novel insights for immunotherapy decision-making in KIRC patients.
摘要：
免疫检查点阻断（ICB）治疗提高了肾肾透明细胞癌（KIRC）的总生存率，但大多数接受治疗的患者未能表现出持久的临床反应。淋巴细胞活化基因-3(LAG3)是一种新型的抑制性免疫检查点,但是它的表达模式，预后价值，在KIRC中的免疫学作用仍然未知。在这项研究中,我们利用TCGA_KIRCRNA测序数据分析了LAG3表达与临床特征之间的关系.采用单细胞测序数据和组织免疫荧光来研究LAG3在KIRC中的亚细胞定位。卡普兰-迈耶绘图仪,TIMER,和TISIDB用于评估LAG3表达与预后之间的关系，以及它与免疫相关成分的相关性。我们使用STRING构建了LAG3交互网络，遗传狂躁症,BioGRID,和HitPredict数据库。我们发现LAG3上调，并与KIRC的不良预后表型相关。LAG3主要在耗尽的CD8+T细胞上表达,并且在KIRC中显示与PDCD1的强共表达。此外，我们的研究结果表明,LAG3不仅抑制T细胞活化,而且可能调节KIRC细胞粘附.总之,我们的研究提示LAG3可作为KIRC的潜在预后生物标志物.此外，同时阻断LAG3和PDCD1可以减轻抗PDCD1治疗的耐药性，为KIRC患者的免疫治疗决策提供新的见解。
