Neddylation and anti-tumor immunity.

Xiaoguang Wang,Alexey V Danilov,Scott Best

doi:10.18632/oncotarget.28019

Xiaoguang Wang, Alexey V Danilov + Show 1 more

Open Access

https://doi.org/10.18632/oncotarget.28019

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Abstract

Contrary to chemotherapy, novel targeted therapies are associated with diverse immunomodulatory effects. Nedd8 is a small ubiquitin-like modifier that is involved in regulation of protein degradation. Neddylation is a promising target in cancer. Pevonedistat, a small molecule inhibitor of the Nedd8-activating enzyme, demonstrates pre-clinical activity in multiple tumor types. Recent studies have revealed that neddylation is important in immunity. We and others have shown that interfering with neddylation causes downstream immunomodulatory effects potentially leading to enhanced anti-tumor immunity. Thus, Nedd8 is a promising target in immuno-oncology.

Highlights

Recent reports have implicated neddylation in regulation of immune cell function, including proliferation, maturation, effector cell function and signal transduction [21,22,23,24,25]
Our group has shown that in vitro exposure to pevonedistat downregulated activation of proximal T-cell receptor (TCR) signaling, accompanied by suppression of NF-κB-regulated genes and IL-2 signaling in T cells derived from patients with chronic lymphocytic leukemia (CLL) [24]
Our results are partially supported by Friend et al who observed that Cullin-RING E3 ubiquitin ligases (CRLs) suppress TCR signaling and IL-2 production in murine T-cell hybridomas, a phenomenon reversed by pevonedistat [25]

Summary

Introduction

Recent reports have implicated neddylation in regulation of immune cell function, including proliferation, maturation, effector cell function and signal transduction [21,22,23,24,25]. Pharmacologic and genetic manipulation of the neddylation pathway has been shown to modulate T-cell mediated immune responses [26]. Genetic knockdown of the Nedd8-conjugating enzyme Ubc12 in murine CD4+ T cells led to diminished proliferation, skewed Th1/Th2 differentiation and reduced cytokine production [21].

Results

Conclusion