The ubiquitin ligase MDM2 sustains STAT5 stability to control T cell-mediated antitumor immunity
dc.contributor.author | Zhou, J | |
dc.contributor.author | Kryczek, I | |
dc.contributor.author | Li, S | |
dc.contributor.author | Li, X | |
dc.contributor.author | Aguilar, A | |
dc.contributor.author | Wei, S | |
dc.contributor.author | Grove, S | |
dc.contributor.author | Vatan, L | |
dc.contributor.author | Yu, J | |
dc.contributor.author | Yan, Y | |
dc.contributor.author | Liao, P | |
dc.contributor.author | Lin, H | |
dc.contributor.author | Li, J | |
dc.contributor.author | Li, G | |
dc.contributor.author | Du, W | |
dc.contributor.author | Wang, W | |
dc.contributor.author | Lang, X | |
dc.contributor.author | Wang, W | |
dc.contributor.author | Wang, S | |
dc.contributor.author | Zou, W | |
dc.coverage.spatial | United States | |
dc.date.accessioned | 2023-12-05T20:05:22Z | |
dc.date.available | 2023-12-05T20:05:22Z | |
dc.date.issued | 2021-04-01 | |
dc.identifier.issn | 1529-2908 | |
dc.identifier.issn | 1529-2916 | |
dc.identifier.uri | https://www.ncbi.nlm.nih.gov/pubmed/33767425 | |
dc.identifier.uri | https://hdl.handle.net/2027.42/191681 | en |
dc.description.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. | |
dc.format.medium | Print-Electronic | |
dc.language | eng | |
dc.publisher | Springer Nature | |
dc.subject | Animals | |
dc.subject | Antineoplastic Agents | |
dc.subject | CD8-Positive T-Lymphocytes | |
dc.subject | Cell Line, Tumor | |
dc.subject | Combined Modality Therapy | |
dc.subject | Female | |
dc.subject | Gene Expression Regulation, Neoplastic | |
dc.subject | HEK293 Cells | |
dc.subject | Humans | |
dc.subject | Immunotherapy, Adoptive | |
dc.subject | Lymphocytes, Tumor-Infiltrating | |
dc.subject | Mice | |
dc.subject | Mice, Inbred BALB C | |
dc.subject | Mice, Inbred C57BL | |
dc.subject | Mice, Transgenic | |
dc.subject | Neoplasms | |
dc.subject | Protein Stability | |
dc.subject | Proteolysis | |
dc.subject | Proto-Oncogene Proteins c-mdm2 | |
dc.subject | STAT5 Transcription Factor | |
dc.subject | Signal Transduction | |
dc.subject | Tumor Suppressor Protein p53 | |
dc.title | The ubiquitin ligase MDM2 sustains STAT5 stability to control T cell-mediated antitumor immunity | |
dc.type | Article | |
dc.identifier.pmid | 33767425 | |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/191681/2/The ubiquitin ligase MDM2 sustains STAT5 stability to control T cell-mediated antitumor immunity.pdf | |
dc.identifier.doi | 10.1038/s41590-021-00888-3 | |
dc.identifier.doi | https://dx.doi.org/10.7302/21861 | |
dc.identifier.source | Nature Immunology | |
dc.description.version | Published version | |
dc.date.updated | 2023-12-05T20:05:18Z | |
dc.identifier.orcid | 0000-0002-3130-2533 | |
dc.identifier.orcid | 0000-0002-2703-5268 | |
dc.identifier.orcid | 0000-0002-8409-5574 | |
dc.identifier.orcid | 0000-0002-8782-6950 | |
dc.identifier.orcid | 0000-0001-7952-3549 | |
dc.description.filedescription | Description of The ubiquitin ligase MDM2 sustains STAT5 stability to control T cell-mediated antitumor immunity.pdf : Published version | |
dc.identifier.volume | 22 | |
dc.identifier.issue | 4 | |
dc.identifier.startpage | 460 | |
dc.identifier.endpage | 470 | |
dc.identifier.name-orcid | Zhou, J | |
dc.identifier.name-orcid | Kryczek, I; 0000-0002-3130-2533 | |
dc.identifier.name-orcid | Li, S | |
dc.identifier.name-orcid | Li, X | |
dc.identifier.name-orcid | Aguilar, A | |
dc.identifier.name-orcid | Wei, S; 0000-0002-2703-5268 | |
dc.identifier.name-orcid | Grove, S | |
dc.identifier.name-orcid | Vatan, L | |
dc.identifier.name-orcid | Yu, J | |
dc.identifier.name-orcid | Yan, Y | |
dc.identifier.name-orcid | Liao, P; 0000-0002-8409-5574 | |
dc.identifier.name-orcid | Lin, H | |
dc.identifier.name-orcid | Li, J | |
dc.identifier.name-orcid | Li, G | |
dc.identifier.name-orcid | Du, W | |
dc.identifier.name-orcid | Wang, W | |
dc.identifier.name-orcid | Lang, X | |
dc.identifier.name-orcid | Wang, W | |
dc.identifier.name-orcid | Wang, S; 0000-0002-8782-6950 | |
dc.identifier.name-orcid | Zou, W; 0000-0001-7952-3549 | |
dc.working.doi | 10.7302/21861 | en |
dc.owningcollname | Surgery, Department of |
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