Mutant p53 suppresses innate immune signaling to promote tumorigenesis

Mutant p53 (mtp53) proteins can exert cancer-promoting gain-of-function activities. We report a mechanism by which mtp53 suppresses both cell-autonomous and non-cell-autonomous signaling to promote cancer cell survival and evasion of tumor immune surveillance. Mtp53 interferes with the function of t...

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Veröffentlicht in:Cancer cell 2021-04, Vol.39 (4), p.494-508.e5
Hauptverfasser: Ghosh, Monisankar, Saha, Suchandrima, Bettke, Julie, Nagar, Rachana, Parrales, Alejandro, Iwakuma, Tomoo, van der Velden, Adrianus W.M., Martinez, Luis A.
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Sprache:eng
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Zusammenfassung:Mutant p53 (mtp53) proteins can exert cancer-promoting gain-of-function activities. We report a mechanism by which mtp53 suppresses both cell-autonomous and non-cell-autonomous signaling to promote cancer cell survival and evasion of tumor immune surveillance. Mtp53 interferes with the function of the cytoplasmic DNA sensing machinery, cGAS-STING-TBK1-IRF3, that activates the innate immune response. Mtp53, but not wild-type p53, binds to TANK-binding protein kinase 1 (TBK1) and prevents the formation of a trimeric complex between TBK1, STING, and IRF3, which is required for activation, nuclear translocation, and transcriptional activity of IRF3. Inactivation of innate immune signaling by mtp53 alters cytokine production, resulting in immune evasion. Restoring TBK1 signaling is sufficient to bypass mtp53 and lead to restored immune cell function and cancer cell eradication. This work is of translational interest because therapeutic approaches that restore TBK1 function could potentially reactivate immune surveillance and eliminate mtp53 tumors. [Display omitted] •Mutant p53 suppresses innate immune signaling and promotes immune evasion•Mutant p53 interacts with TBK1 to prevent STING-IRF3-TBK1 trimeric complex formation•Mutant p53 promotes tumor progression via cell-autonomous and non-autonomous signaling Ghosh et al. show that mutant p53 suppresses downstream signaling from the cGAS/STING cytosolic DNA-sensing pathway by interacting with TANK-binding protein kinase 1 (TBK1), resulting in the attenuation of the type I interferon response and the promotion of tumor growth through immune evasion.
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccell.2021.01.003