| Literature DB >> 33767425 |
Jiajia Zhou1,2, Ilona Kryczek1,2, Shasha Li1,2, Xiong Li1,2, Angelo Aguilar3,4,5, Shuang Wei1,2, Sara Grove1,2, Linda Vatan1,2, Jiali Yu1,2, Yijian Yan1,2, Peng Liao1,2, Heng Lin1,2, Jing Li1,2, Gaopeng Li1,2, Wan Du1,2, Weichao Wang1,2, Xueting Lang1,2, Weimin Wang1,2, Shaomeng Wang3,4,5, Weiping Zou6,7,8,9,10,11.
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.Entities:
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Year: 2021 PMID： 33767425 PMCID： PMC8026726 DOI： 10.1038/s41590-021-00888-3
Source DB: PubMed Journal: Nat Immunol ISSN： 1529-2908 Impact factor: 25.606