Proteolytic regulation of CD73 by TRIM21 orchestrates tumor immunogenicity.
Sci Adv
; 9(1): eadd6626, 2023 01 06.
Article
en En
| MEDLINE
| ID: mdl-36608132
ABSTRACT
Despite the rapid utilization of immunotherapy, emerging challenges to the current immune checkpoint blockade need to be resolved. Here, we report that elevation of CD73 levels due to its aberrant turnover is correlated with poor prognosis in immune-cold triple-negative breast cancers (TNBCs). We have identified TRIM21 as an E3 ligase that governs CD73 destruction. Disruption of TRIM21 stabilizes CD73 that in turn enhances CD73-catalyzed production of adenosine, resulting in the suppression of CD8+ T cell function. Replacement of lysine 133, 208, 262, and 321 residues by arginine on CD73 attenuated CD73 ubiquitylation and degradation. Diminishing of CD73 ubiquitylation remarkably promotes tumor growth and impedes antitumor immunity. In addition, a TRIM21high/CD73low signature in a subgroup of human breast malignancies was associated with a favorable immune profile. Collectively, our findings uncover a mechanism that governs CD73 proteolysis and point to a new therapeutic strategy by modulating CD73 ubiquitylation.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Neoplasias de la Mama Triple Negativas
/
Inmunoterapia
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Sci Adv
Año:
2023
Tipo del documento:
Article
País de afiliación:
Estados Unidos