Kelvin Yin1,2, Daniel Patten3, Sarah Gough1, Susana de Barros Gonçalves1, Adelyne Chan1, Ioana Olan1, Liam Cassidy1, Marta Poblocka1, Haoran Zhu1, Aaron Lun1, Martijn Schuijs1, Andrew Young1, Celia Martinez-Jimenez2, Timotheus Y.F. Halim1, Shishir Shetty3, Masashi Narita1,4 and Matthew Hoare1,5 1Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, United Kingdom; 2Helmholtz Pioneer Campus, Helmholtz Zentrum München, 85764 München, Germany; 3Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, United Kingdom; 4Tokyo Tech World Research Hub Initiative (WRHI), Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, Kanagawa 226-0026, Japan; 5Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, United Kingdom Corresponding authors: mwh20cam.ac.uk, masashi.naritacruk.cam.ac.uk Abstract

Senescence is a stress-responsive tumor suppressor mechanism associated with expression of the senescence-associated secretory phenotype (SASP). Through the SASP, senescent cells trigger their own immune-mediated elimination, which if evaded leads to tumorigenesis. Senescent parenchymal cells are separated from circulating immunocytes by the endothelium, which is targeted by microenvironmental signaling. Here we show that SASP induces endothelial cell NF-κB activity and that SASP-induced endothelial expression of the canonical NF-κB component Rela underpins senescence surveillance. Using human liver sinusoidal endothelial cells (LSECs), we show that SASP-induced endothelial NF-κB activity regulates a conserved transcriptional program supporting immunocyte recruitment. Furthermore, oncogenic hepatocyte senescence drives murine LSEC NF-κB activity in vivo. Critically, we show two distinct endothelial pathways in senescence surveillance. First, endothelial-specific loss of Rela prevents development of Stat1-expressing CD4+ T lymphocytes. Second, the SASP up-regulates ICOSLG on LSECs, with the ICOS–ICOSLG axis contributing to senescence cell clearance. Our results show that the endothelium is a nonautonomous SASP target and an organizing center for immune-mediated senescence surveillance.

Received March 21, 2022. Accepted May 16, 2022.