Neddylation inhibition upregulates PD‐L1 expression and enhances the efficacy of immune checkpoint blockade in glioblastoma. Issue 3 (14th May 2019)

• Record Type: Journal Article
• Authors: Zhou, Shaolong; Zhao, Xinyi; Yang, Zhuo; Yang, Ruyi; Chen, Chao; Zhao, Kailiang; Wang, Weiwei; Ma, Yihui; Zhang, Qiang; Wang, Xinjun
• Is Part Of: International journal of cancer. Volume 145:Issue 3(2019)
• Page Start: 763
• Page End: 774
• Publication Date: 2019-05-14
• Subjects: pevonedistat -- neddylation -- immunotherapy -- PD‐L1 -- glioblastoma; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.32379
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : Pevonedistat (MLN4924), a specific NEDD8‐activating enzyme inhibitor, has been considered as a promising treatment for glioblastoma, which is currently in Phase I/II clinical trials. On the other hand, inhibition of neddylation pathway substantially upregulates the expression of T cell negative regulator programmed death‐ligand 1 (PD‐L1), which might account for the potential resistance via evasion of immune surveillance checkpoints. Whether administration of anti‐PD‐L1 enhances the efficacy of pevonedistat through a cytotoxic T cell‐dependent mechanism in glioblastoma needs to be investigated. Here, we report that depletion of neddylation pathway key enzymes markedly elevates PD‐L1 expression in glioblastoma cancer cells. Consistently, neddylation inhibitor pevonedistat significantly enhances PD‐L1 expression in both glioblastoma cancer cell lines and animal models. Mechanistically, pevonedistat increases PD‐L1 mRNA levels mainly through inhibiting Cullin1‐F‐box and WD repeat domain‐containing 7 E3 ligase activity and accumulating c‐MYC proteins, a direct transcriptional activator of PD‐L1 gene expression. In addition, inhibition of Cullin3 activity by pevonedistat also blocks PD‐L1 protein degradation. Importantly, pevonedistat attenuates T cell killing through PD‐L1 induction, and blockade of PD‐L1 restores the sensitivity of pevonedistat‐treated glioblastoma cancer cells to T cell killing. The combination of pevonedistat and anti‐PD‐L1 therapy compared to each agent alone significantly increased the therapeutic efficacy in vivo . Our study demonstrates inhibition of neddylation pathway suppresses cancer‐associated immunity and provides solid evidence to support the combination of pevonedistat and PD‐L1/programmed cell death protein 1 immune checkpoint blockade as a potential therapeutic strategy to treat glioblastoma. Abstract : What's new? Inhibitors of neddylation, a posttranslational modification that adds the ubiquitin‐like NEDD8 protein to target proteins, are promising cancer therapeutics, but might enhance cancer‐associated immunosuppression. Here the authors show that neddylation inhibitor pevonedistat upregulates programmed death ligand 1 (PD‐L1) expression on glioblastoma cell lines through stabilization of the c‐Myc transcription factor. Blockade of the PD‐L1/PD‐1 interaction potentiates the effect of pevonedistat on glioblastoma cell survival, providing proof‐of‐concept evidence for combining pevonedistat and PD‐L1/PD‐1‐blocking antibodies in future clinical trials.