2023/12/05 by Zhou, J, Kryczek, I, Li, S +16
#Adoptive #Animals #Antineoplastic Agents #CD8-Positive T-Lymphocytes #Cell Line #Combined Modality Therapy #Female #Gene Expression Regulation #HEK293 Cells #Humans #Immunotherapy #Inbred BALB C #Inbred C57BL #Lymphocytes #Mice #Neoplasms #Neoplastic #Protein Stability #Proteolysis #Proto-Oncogene Proteins c-mdm2 #STAT5 Transcription Factor #Signal Transduction #Transgenic #Tumor #Tumor Suppressor Protein p53 #Tumor-Infiltrating
paper · doi:10.7302/21861
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.