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p16-dependent increase of PD-L1 stability regulates immunosurveillance of senescent cells. | LitMetric

AI Article Synopsis

  • Senescent cells contribute to aging and diseases but avoid elimination by the immune system, which is not fully understood.
  • This study highlights that p16-positive senescent cells increase the immune checkpoint protein PD-L1, allowing them to persist in aging and inflamed tissues.
  • By targeting PD-L1 with specific antibodies, researchers can remove these senescent cells, suggesting a potential strategy to boost immune responses and reduce related inflammation.

Article Abstract

The accumulation of senescent cells promotes ageing and age-related diseases, but molecular mechanisms that senescent cells use to evade immune clearance and accumulate in tissues remain to be elucidated. Here we report that p16-positive senescent cells upregulate the immune checkpoint protein programmed death-ligand 1 (PD-L1) to accumulate in ageing and chronic inflammation. We show that p16-mediated inhibition of cell cycle kinases CDK4/6 induces PD-L1 stability in senescent cells via downregulation of its ubiquitin-dependent degradation. p16-expressing senescent alveolar macrophages elevate PD-L1 to promote an immunosuppressive environment that can contribute to an increased burden of senescent cells. Treatment with activating anti-PD-L1 antibodies engaging Fcγ receptors on effector cells leads to the elimination of PD-L1 and p16-positive cells. Our study uncovers a molecular mechanism of p16-dependent regulation of PD-L1 protein stability in senescent cells and reveals the potential of targeting PD-L1 to improve immunosurveillance of senescent cells and ameliorate senescence-associated inflammation.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11321988PMC
http://dx.doi.org/10.1038/s41556-024-01465-0DOI Listing

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