Pharmacologic targeting of Nedd8-activating enzyme reinvigorates T-cell responses in lymphoid neoplasia.

ABSTRACT: Neddylation is a sequential enzyme-based process which regulates the function of E3 Cullin-RING ligase (CRL) and thus degradation of substrate proteins. Here we show that CD8⁺ T cells are a direct target for therapeutically relevant anti-lymphoma activity of pevonedistat, a Nedd8-activating enzyme (NAE) inhibitor. Pevonedistat-treated patient-derived CD8⁺ T cells upregulated TNFα and IFNγ and exhibited enhanced cytotoxicity. Pevonedistat induced CD8⁺ T-cell inflamed microenvironment and delayed tumor progression in A20 syngeneic lymphoma model. This anti-tumor effect lessened when CD8⁺ T cells lost the ability to engage tumors through MHC class I interactions, achieved either through CD8⁺ T-cell depletion or genetic knockout of B2M. Me

SUBMITTER: Wang X 

PROVIDER: S-EPMC10244170 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature