浙江大学杨波等研究人员合作发现，IMPDH抑制剂在癌细胞中上调PD-L1表达但不影响免疫检查点抑制剂的疗效。2024年11月26日，《中国药理学报》杂志在线发表了这项成果。

研究人员探讨了肌苷酸5’-单磷酸脱氢酶（IMPDH）是否参与癌症免疫调节。研究人员发现，IMPDH抑制剂AVN944、MPA或利巴韦林能够浓度依赖性地上调非小细胞肺癌细胞系NCI-H292中的PD-L1表达。该效应在其他非小细胞肺癌细胞系H460、H1299和HCC827、结肠癌细胞系HT29、RKO和HCT116，以及肾癌细胞系Huh7中得到了重现。

在NCI-H292细胞中，研究人员明确了IMPDH抑制剂通过增强CD274 mRNA稳定性增加了CD274 mRNA水平。IMPDH抑制剂提高了ARE结合蛋白HuR与CD274 mRNA的亲和力，从而稳定了CD274 mRNA。鸟苷的补充消除了IMPDH抑制剂引起的PD-L1表达增加。

在用于免疫检查点抑制剂（ICI）研究的CT26和EMT6肿瘤模型中，研究人员发现尽管IMPDH抑制剂具有免疫抑制作用，但它并未减少免疫检查点抑制剂的临床反应。这一重要临床观察值得注意，因为这一类药物已获批用于多种疾病。研究人员得出结论，PD-L1的诱导有助于IMPDH抑制剂的免疫抑制效应。此外，IMPDH抑制剂硫唑嘌呤并不会对免疫检查点抑制产生拮抗作用。

研究人员表示，肿瘤细胞的特点是快速增殖。为了提供DNA和RNA合成所需的嘌呤，IMPDH作为新生鸟苷合成中的关键酶在肿瘤细胞中高度表达。

附：英文原文

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

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

Issue&Volume: 2024-11-26

Abstract: 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.

DOI: 10.1038/s41401-024-01411-8

Source: https://www.nature.com/articles/s41401-024-01411-8