Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2023.01.30.524522v1?rss=1

Authors: 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.

Abstract:
The accumulation of senescent cells promotes aging, but the 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 increased burden of senescent cells. Treatment with immunostimulatory anti-PD-L1 antibody enhances the cytotoxic T cell activity and leads to 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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