Jin Yigang, Zhang Qihui, Wang Fei, Wu Yuntao, Guo Xiao
Department of Urology, Jiaxing Second Hospital, Jiaxing 314000, China.
Department of Urology, Jiaxing Second Hospital, Jiaxing 314000, China.
Hum Immunol. 2025 Jan;86(1):111223. doi: 10.1016/j.humimm.2024.111223. Epub 2025 Jan 3.
Previous studies have revealed the essential role of lysosomes in human diseases, including cancer. However, there is a lack of in-depth systematic research on its function in kidney renal clear cell carcinoma (KIRC). In this project, we collected the public dataset of KIRC and selected lysosomal genes tightly linked with survival. Cluster analysis uncovered that these genes possess good classification ability and can divide KIRC patients into multiple subtypes with different survival rates. Enrichment analyses revealed that the main biological processes associated with differentially expressed genes (DEGs) in the two representative subpopulations with the largest survival differences (cluster1 and cluster2) were steroid metabolic process, neutrophil extracellular trap formation, and tyrosine metabolism. The immune-related analysis demonstrated notable differences in immune cell infiltration levels between cluster1 and cluster2 subpopulations of KIRC. More specifically, Tfh and TIL were highly infiltrated in the cluster1, and Type II IFN response, mast cells, and basophils were highly infiltrated in the cluster2. The immunotherapy-related analysis demonstrated that cluster1 may be more sensitive to immunotherapy and more likely to benefit from immunotherapy due to its higher immune checkpoint expression, ESTIMATE score, immune score, and higher immunophenoscore (IPS). In addition, gene mutations occurred in the two subtypes, exhibiting similar mutation patterns between the two subtypes. Finally, based on the cMAP database, we identified some small molecules that may target DEGs between the two subtypes, such as epibatidine, mepyramine, and reboxetine. In conclusion, our investigation unearthed that different subtypes of KIRC patients exhibited different survival outcomes and sensitivity to the immune microenvironment, as well as different responses to immunotherapy. These findings may be beneficial for further mechanistic exploration and therapeutic research of KIRC in the future.
先前的研究已经揭示了溶酶体在包括癌症在内的人类疾病中的重要作用。然而，对于其在肾透明细胞癌（KIRC）中的功能缺乏深入的系统研究。在本项目中，我们收集了KIRC的公共数据集，并选择了与生存紧密相关的溶酶体基因。聚类分析发现这些基因具有良好的分类能力，能够将KIRC患者分为具有不同生存率的多个亚型。富集分析表明，在生存差异最大的两个代表性亚群（cluster1和cluster2）中，与差异表达基因（DEGs）相关的主要生物学过程是类固醇代谢过程、中性粒细胞胞外陷阱形成和酪氨酸代谢。免疫相关分析显示，KIRC的cluster1和cluster2亚群之间免疫细胞浸润水平存在显著差异。更具体地说，Tfh和TIL在cluster1中高度浸润，而II型干扰素反应、肥大细胞和嗜碱性粒细胞在cluster2中高度浸润。免疫治疗相关分析表明，cluster1可能对免疫治疗更敏感，并且由于其较高的免疫检查点表达、ESTIMATE评分、免疫评分和较高的免疫表型评分（IPS），更有可能从免疫治疗中获益。此外，两个亚型中均发生了基因突变，两个亚型之间表现出相似的突变模式。最后，基于cMAP数据库，我们鉴定了一些可能靶向两个亚型之间DEGs的小分子，如埃博霉素、美吡拉敏和瑞波西汀。总之，我们的研究发现，KIRC患者的不同亚型表现出不同的生存结果和对免疫微环境的敏感性，以及对免疫治疗的不同反应。这些发现可能有助于未来对KIRC进行进一步的机制探索和治疗研究。
