Wang Jiaxin, Lin Jie, Guo Huaijuan, Wu Wenjuan, Yang Jingjing, Mao Jingxian, Fan Wenbin, Qiao Hong, Wang Ying, Yan Xuebing, Guo Hong
Department of Oncology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu, China.
Department of Hepatobiliary and Pancreatic Surgery, Jilin University Second Hospital, Changchun, Jilin, China.
Front Pharmacol. 2024 Jul 29;15:1419498. doi: 10.3389/fphar.2024.1419498. eCollection 2024.
Metformin as a common antidiabetic drug, has recently found to exert its anti-cancer and immunomodulatory effect in numerous preclinical studies. This study aims to clarify the prognostic impact of metformin use in solid cancer patients receiving immune checkpoint inhibitors (ICIs). A retrospective cohort enrolling 516 solid cancer patients who received ICI-based therapy between 2018 and 2023 at three hospitals was analyzed. The primary endpoints included overall survival (OS) and progression-free survival (PFS). In addition, a bioinformatics analysis based on TCGA and GSE cohort was performed to investigate the prognostic significance of metformin target genes (MTGs) and their correlation with immune infiltration in non-small cell lung cancer (NSCLC) patients. In the entire cohort, a total of 76 patients received metformin before and/or during ICI therapy. The global analysis demonstrated that metformin use was unrelated with the OS ( = 0.064) and PFS ( = 0.059) of ICI-treated cancer patients, which was confirmed in the subgroups of esophagus, hepatobiliary or pancreatic cancer (all > 0.05). However, metformin use was significantly correlated with better OS ( = 0.012) and PFS ( = 0.005) in ICI-treated lung cancer patients. Metformin use was also identified as an independent favorable prognostic factor for these patients. The bioinformatics analysis identified five favorable prognostic MTGs (RPS6KA5, RORA, SH3BP5, NUPR1, and CD40LG) for NSCLC patients, all of which was downregulated in lung cancer tissues as compared with normal tissues. The expressions of five MTGs not only could effectively stratify the OS of NSCLC patients, but also was correlated with infiltration of immune cells such as CD4 and CD8 T cells. Metformin use was significantly correlated with better OS and PFS in ICI-treated lung cancer patients. MTGs has the potential to serve as novel clinical biomarkers or druggable targets for cancer immunotherapy. Considering study limitations, the actual impact of metformin use on ICI therapy needs to be clarified by more clinical trials.
二甲双胍作为一种常见的抗糖尿病药物，最近在众多临床前研究中发现具有抗癌和免疫调节作用。本研究旨在阐明二甲双胍在接受免疫检查点抑制剂（ICI）治疗的实体癌患者中的预后影响。分析了一个回顾性队列，该队列纳入了2018年至2023年期间在三家医院接受基于ICI治疗的516例实体癌患者。主要终点包括总生存期（OS）和无进展生存期（PFS）。此外，基于TCGA和GSE队列进行了生物信息学分析，以研究二甲双胍靶基因（MTGs）在非小细胞肺癌（NSCLC）患者中的预后意义及其与免疫浸润的相关性。在整个队列中，共有76例患者在ICI治疗前和/或治疗期间服用了二甲双胍。整体分析表明，二甲双胍的使用与接受ICI治疗的癌症患者的OS（P = 0.064）和PFS（P = 0.059）无关，这在食管癌、肝胆癌或胰腺癌亚组中得到证实（所有P均>0.05）。然而，在接受ICI治疗的肺癌患者中，二甲双胍的使用与更好的OS（P = 0.012）和PFS（P = 0.005）显著相关。二甲双胍的使用也被确定为这些患者的独立有利预后因素。生物信息学分析确定了NSCLC患者的五个有利预后MTGs（RPS6KA5、RORA、SH3BP5、NUPR1和CD40LG），与正常组织相比，所有这些基因在肺癌组织中均下调。五个MTGs的表达不仅可以有效分层NSCLC患者的OS，还与CD4和CD8 T细胞等免疫细胞的浸润相关。在接受ICI治疗的肺癌患者中，二甲双胍的使用与更好的OS和PFS显著相关。MTGs有潜力作为癌症免疫治疗的新型临床生物标志物或可成药靶点。考虑到研究局限性，二甲双胍使用对ICI治疗的实际影响需要更多临床试验来阐明。
