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

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-? 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.
Mesh Terms:
Animals, Antineoplastic Agents, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Combined Modality Therapy, Female, Gene Expression Regulation, Neoplastic, HEK293 Cells, Humans, Immunotherapy, Adoptive, Lymphocytes, Tumor-Infiltrating, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Neoplasms, Protein Stability, Proteolysis, Proto-Oncogene Proteins c-mdm2, STAT5 Transcription Factor, Signal Transduction, Tumor Suppressor Protein p53
Nat Immunol
Date: Dec. 01, 2020
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