Xu Tao, Wang Zhen, Liu Jiahao, Wang Ge, Zhou Dongchen, Du Yaying, Li Xingrui, Xia Yu, Gao Qinglei
Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Front Oncol. 2022 Jun 8;12:820696. doi: 10.3389/fonc.2022.820696. eCollection 2022.
Immunotherapy is the most promising treatment in triple-negative breast cancer (TNBC), and its efficiency is largely dependent on the intra-tumoral immune cells infiltrations. Thus, novel ways to assist immunotherapy by increasing immune cell infiltrations were highly desirable.
To find key immune-related genes and discover novel immune-evoking molecules, gene expression profiles of TNBC were downloaded from Gene Expression Omnibus (GEO). Single-sample gene set enrichment analysis (ssGSEA) and Weighted Gene Co-expression Network Analysis (WGCNA) were conducted to identified hub genes. The CMap database was used subsequently to predicate potential drugs that can modulate the overall hub gene expression network. experiments were conducted to assess the anti-tumor activity and the pyroptosis phenotypes induced by GW-8510.
Gene expression profiles of 198 TNBC patients were downloaded from GEO dataset GSE76124, and ssGSEA was used to divide them into Immune Cell Proficiency (ICP) group and Immune Cell Deficiency (ICD) group. Hub differential expressed gene modules between two groups were identified by WGCNA and then annotated by Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. A cyclin-dependent kinase (CDK) 2 inhibitor, GW-8510 was then identified by the CMap database and further investigated. Treatment with GW-8510 resulted in potent inhibition of TNBC cell lines. More importantly, and studies confirmed that GW-8510 and other CDK inhibitors (Dinaciclib, and Palbociclib) can induce pyroptosis by activating caspase-3 and GSDME, which might be the mechanism for their immune regulation potentials.
GW-8510, as well as other CDK inhibitors, might serve as potential immune regulators and pyroptosis promotors in TNBC.
免疫疗法是三阴性乳腺癌（TNBC）最有前景的治疗方法，其疗效在很大程度上取决于肿瘤内免疫细胞浸润。因此，非常需要通过增加免疫细胞浸润来辅助免疫疗法的新方法。
为了找到关键的免疫相关基因并发现新的免疫激发分子，从基因表达综合数据库（GEO）下载了TNBC的基因表达谱。进行单样本基因集富集分析（ssGSEA）和加权基因共表达网络分析（WGCNA）以鉴定枢纽基因。随后使用CMap数据库预测可调节整体枢纽基因表达网络的潜在药物。进行实验以评估GW-8510诱导的抗肿瘤活性和细胞焦亡表型。
从GEO数据集GSE76124下载了198例TNBC患者的基因表达谱，并使用ssGSEA将他们分为免疫细胞丰富（ICP）组和免疫细胞缺陷（ICD）组。通过WGCNA鉴定两组之间的枢纽差异表达基因模块，然后通过基因本体（GO）注释和京都基因与基因组百科全书（KEGG）通路富集分析进行注释。然后通过CMap数据库鉴定出一种细胞周期蛋白依赖性激酶（CDK）2抑制剂GW-8510，并进行进一步研究。用GW-8510处理导致TNBC细胞系受到有效抑制。更重要的是， 和 研究证实GW-8510和其他CDK抑制剂（Dinaciclib和Palbociclib）可通过激活半胱天冬酶-3和GSDME诱导细胞焦亡，这可能是它们具有免疫调节潜力的机制。
GW-8510以及其他CDK抑制剂可能作为TNBC潜在的免疫调节剂和细胞焦亡促进剂。
