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Cancer Res. 2018 Dec 1;78(23):6621-6631. doi: 10.1158/0008-5472.CAN-18-0545. Epub 2018 Sep 13.

Nedd4-Binding Protein 1 and TNFAIP3-Interacting Protein 1 Control MHC-1 Display in Neuroblastoma.

Author information

1
Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands.
2
Department of Biochemistry, Netherlands Cancer Institute, Amsterdam, the Netherlands.
3
Oncode Institute, Netherlands Cancer Institute, Amsterdam, the Netherlands.
4
Proteomics facility, Netherlands Cancer Institute, Amsterdam, the Netherlands.
5
Biomolecular Mass Spectrometry and Proteomics, Utrecht Institute for Pharmaceutical Sciences, Utrecht, the Netherlands.
6
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
7
Cancergenomics.nl, Amsterdam, the Netherlands.
8
Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands. M.L.Boes@umcutrecht.nl.
#
Contributed equally

Abstract

: Neuroblastoma is the second most common tumor in children. The cause of neuroblastoma is thought to lie in aberrant development of embryonic neural crest cells and is accompanied by low MHC-1 expression and suppression of the NF-κB transcription factor, thereby gearing cells toward escape from immunosurveillance. Here, we assess regulation of the MHC-1 gene in neuroblastoma to enhance its immunogenic potential for therapeutic T-cell targeting. A genome-wide CRISPR screen identified N4BP1 and TNIP1 as inhibitory factors of NF-κB-mediated MHC-1 expression in neuroblastoma. Patients with advanced stage neuroblastoma who expressed high levels of TNIP1 and N4BP1 exhibited worse overall survival. Depletion of N4BP1 or TNIP1 increased NF-κB and MHC-1 expression and stimulated recognition by antigen-specific CD8+ T cells. We confirmed that TNIP1 inhibited canonical NF-κB member RelA by preventing activation of the RelA/p50 NF-κB dimer. Furthermore, N4BP1 inhibited both canonical and noncanonical NF-κB through binding of deubiquitinating enzyme CEZANNE, resulting in stabilization of TRAF3 and degradation of NF-κB-inducing kinase NIK. These data suggest that N4BP1/CEZANNE or TNIP1 may be candidate targets for immunotherapy in neuroblastoma tumors and should lift NF-κB suppression, thereby triggering increased peptide/MHC1-mediated tumor reactivity to enhance therapeutic T-cell targeting. SIGNIFICANCE: Aberrant regulation of NF-κB and MHC-1 in neuroblastoma tumors provides new targets for immunotherapeutic approaches against neuroblastoma.

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