2. Academic Validation
  3. PD-L1 induction via the MEK-JNK-AP1 axis by a neddylation inhibitor promotes cancer-associated immunosuppression

PD-L1 induction via the MEK-JNK-AP1 axis by a neddylation inhibitor promotes cancer-associated immunosuppression

  • Cell Death Dis. 2022 Oct 3;13(10):844. doi: 10.1038/s41419-022-05292-9.
Shizhen Zhang 1 2,  Xiahong You 3,  Tiantian Xu 3,  Qian Chen 3,  Hua Li 4,  Longyu Dou 3,  Yilun Sun 4,  Xiufang Xiong 1 3,  Morgan A Meredith 4,  Yi Sun 5 6 7 8
Affiliations

Affiliations

  • 1 Cancer Institute, the Second Affiliated Hospital, Zhejiang University School of Medicine, 310029, Hangzhou, China.
  • 2 Department of Breast Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, the Second Affiliated Hospital, Zhejiang University School of Medicine, 310029, Hangzhou, China.
  • 3 Institute of Translational Medicine, Zhejiang University School of Medicine, 310029, Hangzhou, China.
  • 4 Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, 4424B MS-1, 1301 Catherine Street, Ann Arbor, MI, 48109, USA.
  • 5 Cancer Institute, the Second Affiliated Hospital, Zhejiang University School of Medicine, 310029, Hangzhou, China. yisun@zju.edu.cn.
  • 6 Institute of Translational Medicine, Zhejiang University School of Medicine, 310029, Hangzhou, China. yisun@zju.edu.cn.
  • 7 Zhejiang University Cancer Center, 310029, Hangzhou, China. yisun@zju.edu.cn.
  • 8 Research Center for Life Science and Human Health, Binjiang Institute of Zhejiang University, Hangzhou, 310053, Zhejiang, China. yisun@zju.edu.cn.
PMID: 36192389 DOI: 10.1038/s41419-022-05292-9
Abstract

MLN4924 is a first-in-class small molecule inhibitor of NEDD8-activating Enzyme (NAE), which is currently in several clinical trials for anti-cancer applications. However, MLN4924 also showed some off-target effects with potential to promote the growth of Cancer cells which counteracts its Anticancer activity. In this study, we found that MLN4924 increases the levels of PD-L1 mRNA and protein in dose- and time-dependent manners. Mechanistic study showed that this MLN4924 effect is largely independent of neddylation inactivation, but is due to activation of both ERK and JNK signals, leading to AP-1 activation, which is blocked by the small molecule inhibitors of MEK and JNK, respectively. Biologically, MLN4924 attenuates T cell killing in a co-culture model due to PD-L1 upregulation, which can be, at least in part, abrogated by either MEK Inhibitor or anti-PD-L1 antibody. In an in vivo BALB/c mouse xenograft tumor model, while MLN4924 alone had no effect, combination with either MEK Inhibitor or anti-PD-L1 antibody enhanced the suppression of tumor growth. Taken together, our study provides a sound rationale for effective Anticancer therapy in combination of anti-PD-L1 antibody or MEK Inhibitor with MLN4924 to overcome the side-effect of immunosuppression by MLN4924 via PD-L1 induction.

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