p16-dependent upregulation of PD-L1 impairs immunosurveillance of senescent cells

Majewska, J.; Agrawal, A.; Mayo, A.; Roitman, L.; Chatterjee, R.; Kralova, J.; Landsberger, T.; Katzenelenbogen, Y.; Salame, T. M.; Hagai, E.; Stanojevic, N.; Amit, I.; Alon, U.; Krizhanovsky, V.

doi:10.1101/2023.01.30.524522

bioRxiv · 10.1101/2023.01.30.524522

p16-dependent upregulation of PD-L1 impairs immunosurveillance of senescent cells

Majewska, J.·Agrawal, A.·Mayo, A.·Roitman, L.·Chatterjee, R.·Kralova, J.·Landsberger, T.·Katzenelenbogen, Y.·Salame, T. M.·Hagai, E.·Stanojevic, N.·Amit, I.·Alon, U.·Krizhanovsky, V.

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Abstract

The accumulation of senescent cells promotes aging, but a molecular mechanism that senescent cells use to evade immune clearance and accumulate remains 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 aging and chronic inflammation. p16-mediated inhibition of CDK4/6 promotes PD-L1 stability in senescent cells via the downregulation of ubiquitin-dependent degradation. p16 expression in infiltrating macrophages induces an immunosuppressive environment that can contribute to an increased burden of senescent cells. Treatment with immunostimulatory anti-PD-L1 antibody enhances the cytotoxic T cell activity and leads to the elimination of p16, PD-L1-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 PD-L1 as a target for treating senescence-mediated age-associated diseases.

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Majewska, J., Agrawal, A., Mayo, A., Roitman, L., Chatterjee, R., Kralova, J., Landsberger, T., Katzenelenbogen, Y., Salame, T. M., Hagai, E., Stanojevic, N., Amit, I., Alon, U., Krizhanovsky, V.. 2023-02-01. p16-dependent upregulation of PD-L1 impairs immunosurveillance of senescent cells. https://doi.org/10.1101/2023.01.30.524522

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