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  • The ubiquitin ligase MDM2 sustains STAT5 stability to control T cell-mediated antitumor immunity.

The ubiquitin ligase MDM2 sustains STAT5 stability to control T cell-mediated antitumor immunity.

Nature immunology (2021-03-27)
Jiajia Zhou, Ilona Kryczek, Shasha Li, Xiong Li, Angelo Aguilar, Shuang Wei, Sara Grove, Linda Vatan, Jiali Yu, Yijian Yan, Peng Liao, Heng Lin, Jing Li, Gaopeng Li, Wan Du, Weichao Wang, Xueting Lang, Weimin Wang, Shaomeng Wang, Weiping Zou
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
MG-132, Ready Made Solution, ≥90% (HPLC)
Sigma-Aldrich
Monoclonal Anti-MDM2 antibody produced in mouse, clone SMP14, ascites fluid