The ubiquitin ligase MDM2 sustains STAT5 stability to control T cell-mediated antitumor immunity.
Nat Immunol
; 22(4): 460-470, 2021 04.
Article
em En
| MEDLINE
| ID: mdl-33767425
ABSTRACT
Targeting the p53-MDM2 pathway to reactivate tumor p53 is a chemotherapeutic approach. However, the involvement of this pathway in CD8+ T cell-mediated antitumor immunity is unknown. Here, we report that mice with MDM2 deficiency in T cells exhibit accelerated tumor progression and a decrease in tumor-infiltrating CD8+ T cell survival and function. Mechanistically, MDM2 competes with c-Cbl for STAT5 binding, reduces c-Cbl-mediated STAT5 degradation and enhances STAT5 stability in tumor-infiltrating CD8+ T cells. Targeting the p53-MDM2 interaction with a pharmacological agent, APG-115, augmented MDM2 in T cells, thereby stabilizing STAT5, boosting T cell immunity and synergizing with cancer immunotherapy. Unexpectedly, these effects of APG-115 were dependent on p53 and MDM2 in T cells. Clinically, MDM2 abundance correlated with T cell function and interferon-γ signature in patients with cancer. Thus, the p53-MDM2 pathway controls T cell immunity, and targeting this pathway may treat patients with cancer regardless of tumor p53 status.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Linfócitos do Interstício Tumoral
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Linfócitos T CD8-Positivos
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Proteínas Proto-Oncogênicas c-mdm2
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Fator de Transcrição STAT5
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Neoplasias
Limite:
Animals
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Female
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Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article