Editors' ChoiceCancer Immunology

Cloaked by mutant p53

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Science Signaling  11 May 2021:
Vol. 14, Issue 682, eabj3463
DOI: 10.1126/scisignal.abj3463

Mutant p53 takes the STING out of antitumor immunity.

Mutant p53 protein drives the growth of many types of cancers. Ghosh et al. found that, in addition to its known tumor-autonomous roles in promoting cell survival, mutant p53 functioned through a non-autonomous mechanism to evade tumor immune surveillance. Mutations in p53 correlate with chromosomal instability, micronuclei, and cytoplasmic DNA, the latter of which can trigger the innate immune response. However, in various cancer cell lines of human and mouse origin, the authors found that mutant p53 (but not wild-type p53) bound to the kinase TBK1, which prevented the formation of a trimeric complex between TBK1, the cytosolic DNA–sensing pathway protein STING, and the transcription factor IRF3 that triggers an innate immune response. In immunocompetent mice bearing syngeneic tumors, the expression of mutant p53 induced altered cytokine profiles (including, critically, reduced secretion of the cytokine IFN-β1), a more tumor-permissive immune cell profile, and accelerated tumor growth. However, the accelerated tumor growth was lost when tumors were implanted in immunodeficient mice. Furthermore, the growth, cytokine, and immune landscape effects of mutant p53 expression in tumors in immunocompetent mice were blocked by concurrent overexpression of TBK1. Supporting correlations between mutant p53 and reduced IFNB1 expression were observed in human triple-negative breast cancer data from the TCGA. These findings not only show a non-autonomous function of mutant p53 in tumor growth, but also suggest that developing TBK1 pathway–restoring therapeutics might be a way to reestablish antitumor immunity in patients. They also indicate a need to consider p53 status in the use of STING agonists, which are currently in early-phase clinical trials for cancer patients, and maybe accordingly revisit the results of those trials that were terminated for lack of efficacy based on progression-free survival.

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