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Yeast As a Chassis for Developing Functional Assays to Study Human P53
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Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

9.8K

Mutant p53 suppresses innate immune signaling to promote tumorigenesis

Monisankar Ghosh1, Suchandrima Saha1, Julie Bettke2

  • 1Stony Brook Cancer Center, Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11790, USA.

Cancer Cell
|February 5, 2021
PubMed

Insights

Mutant p53 (mtp53) suppresses innate immune signaling by inhibiting TBK1, promoting cancer cell survival and immune evasion. Restoring TBK1 function can eliminate mtp53 tumors by reactivating anti-tumor immunity.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Mutant p53 (mtp53) proteins possess cancer-promoting gain-of-function activities.
  • Cancer cells utilize various mechanisms to evade immune surveillance and promote survival.
  • The innate immune system, particularly the cGAS-STING-TBK1-IRF3 pathway, plays a crucial role in anti-tumor immunity.

Purpose of the Study:

  • To elucidate the mechanism by which mtp53 promotes cancer cell survival and immune evasion.
  • To investigate the interaction between mtp53 and the cytoplasmic DNA sensing machinery.
  • To explore therapeutic strategies targeting mtp53-mediated immune suppression.

Main Methods:

  • Investigated the interaction of mtp53 with components of the cGAS-STING-TBK1-IRF3 pathway.
  • Assessed the effect of mtp53 on TBK1 complex formation with STING and IRF3.
  • Analyzed changes in cytokine production and IRF3 transcriptional activity.
  • Evaluated the impact of restoring TBK1 signaling on cancer cell eradication.

Main Results:

  • Mutant p53 (mtp53), unlike wild-type p53, binds to TANK-binding protein kinase 1 (TBK1).
  • Mtp53 binding prevents the formation of the essential TBK1-STING-IRF3 complex, inhibiting IRF3 activation and nuclear translocation.
  • This interference with innate immune signaling leads to altered cytokine production and immune evasion by cancer cells.
  • Restoration of TBK1 signaling effectively bypasses mtp53's suppressive effects, leading to restored immune cell function and cancer cell eradication.

Conclusions:

  • Mutant p53 actively suppresses innate immune signaling through direct inhibition of the TBK1-STING-IRF3 axis.
  • Mtp53-mediated immune suppression contributes to cancer cell survival and evasion of tumor immunity.
  • Therapeutic strategies aimed at restoring TBK1 signaling hold promise for reactivating anti-tumor immune responses and eliminating mtp53-driven cancers.
Keywords:
IRF3STINGTBK1immune evasioninnate immune signalingmutant p53

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