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Purification of Ubiquitinated p53 Proteins from Mammalian Cells
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Purification of Ubiquitinated p53 Proteins from Mammalian Cells

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

Jiajia Zhou1,2, Ilona Kryczek1,2, Shasha Li1,2

  • 1Department of Surgery, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA.

Nature Immunology
|March 26, 2021
PubMed

Insights

The p53-MDM2 pathway regulates CD8+ T cell immunity. Targeting this pathway with APG-115 enhances T cell function and cancer immunotherapy, regardless of tumor p53 status.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • The p53-MDM2 pathway is a target for cancer chemotherapy.
  • The role of this pathway in CD8+ T cell-mediated antitumor immunity remains unclear.

Purpose of the Study:

  • To investigate the role of the p53-MDM2 pathway in T cell-mediated antitumor immunity.
  • To explore the potential of targeting this pathway for cancer immunotherapy.

Main Methods:

  • Mice with T cell-specific MDM2 deficiency were used to study tumor progression and CD8+ T cell function.
  • The effects of the p53-MDM2 inhibitor APG-115 on T cells and tumor immunity were evaluated.
  • Correlation between MDM2 levels, T cell function, and interferon-gamma signature in cancer patients was analyzed.

Main Results:

  • MDM2 deficiency in T cells led to accelerated tumor growth and impaired CD8+ T cell survival and function.
  • MDM2 stabilizes STAT5 in CD8+ T cells by competing with c-Cbl for binding, thus preventing STAT5 degradation.
  • APG-115 treatment enhanced T cell immunity, boosted STAT5 stability, and showed synergy with cancer immunotherapy, dependent on T cell p53 and MDM2.
  • Clinical data showed MDM2 abundance correlates with T cell function and interferon-gamma signature in cancer patients.

Conclusions:

  • The p53-MDM2 pathway is a critical regulator of CD8+ T cell-mediated antitumor immunity.
  • Targeting the p53-MDM2 interaction with agents like APG-115 can enhance T cell immunity and synergize with cancer immunotherapy.
  • This approach holds promise for treating cancer patients irrespective of their tumor's p53 status.

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