IMPDH inhibitors upregulate PD-L1 in cancer cells without impairing immune checkpoint inhibitor efficacy  

作　　者：Ming-ming Zheng Jia-yi Li Hong-jie Guo Jie Zhang Long-sheng Wang Ke-fan Jiang Hong-hai Wu Qiao-jun He Ling Ding Bo Yang 

机构地区：[1]Zhejiang Province Key Laboratory of Anti-Cancer Drug Research,Institute of Pharmacology and Toxicology,College of Pharmaceutical Sciences,Zhejiang University,Hangzhou,310058,China [2]The Innovation Institute for Artificial Intelligence in Medicine,Zhejiang University,Hangzhou,310018,China [3]Cancer Center of Zhejiang University,Hangzhou,310058,China [4]Nanhu Brain-Computer Interface Institute,Hangzhou,311100,China [5]School of Medicine,Hangzhou City University,Hangzhou,310015,China

出　　处：《Acta Pharmacologica Sinica》2025年第4期1058-1067,共10页中国药理学报(英文版)

基　　金：supported by the National Natural Science Foundation of China(No.82330114 to QJH,and No.82273949 to LD).

摘　　要：Tumor cells are characterized by rapid proliferation.In order to provide purines for DNA and RNA synthesis,inosine 5’-monophosphate dehydrogenase(IMPDH),a key enzyme in the de novo guanosine biosynthesis,is highly expressed in tumor cells.In this study we investigated whether IMPDH was involved in cancer immunoregulation.We revealed that the IMPDH inhibitors AVN944,MPA or ribavirin concentration-dependently upregulated PD-L1 expression in non-small cell lung cancer cell line NCI-H292.This effect was reproduced in other non-small cell lung cancer cell lines H460,H1299 and HCC827,colon cancer cell lines HT29,RKO and HCT116,as well as kidney cancer cell line Huh7.In NCI-H292 cells,we clarified that IMPDH inhibitors increased CD274 mRNA levels by enhancing CD274 mRNA stability.IMPDH inhibitors improved the affinity of the ARE-binding protein HuR for CD274 mRNA,thereby stabilizing CD274 mRNA.Guanosine supplementation abolished the IMPDH inhibitor-induced increase in PD-L1 expression.In CT26 and EMT6 tumor models used for ICIs based studies,we showed that despite its immunosuppressive properties,the IMPDH inhibitor mycophenolate mofetil did not reduce the clinical response of checkpoint inhibitors,representing an important clinical observation given that this class of drugs is approved for use in multiple diseases.We conclude that PD-L1 induction contributes to the immunosuppressive effect of IMPDH inhibitors.Furthermore,the IMPDH inhibitor mycophenolate mofetil does not antagonize immune checkpoint blockade.

关 键 词：non-small cell lung IMPDH inhibitors PD-L1 mRNA stability HUR immune checkpoint blockade 

分 类 号：R730.51[医药卫生—肿瘤]