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

Affiliations
  • 1Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. julia.majewska@weizmann.ac.il.
  • 2Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
  • 3Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel.
  • 4Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel.
  • 5Department of Biological Services, Weizmann Institute of Science, Rehovot, Israel.
  • 6Institute for Stem Cell Biology, RWTH Aachen University Medical School, Aachen, Germany.
  • 7Helmholtz Institute for Biomedical Engineering, RWTH Aachen University Medical School, Aachen, Germany.
  • 8Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. valery.krizhanovsky@weizmann.ac.il.

Published on:

August 5, 2024

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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