Senescence-induced endothelial phenotypes underpin immune-mediated senescence surveillance

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.

Endothelial cells give a boost to senescence surveillance

“…Might this alter their immune-recruitment functions, ultimately contributing to senescence accumulation during aging? Overall, the study by Yin et al (2022) provides one more important clue into the complex biology of senescent cells and reinforces the idea that functionally manipulating them—or now their instructed neighbors—could be useful in tumor and aging contexts.…”

“…However, it was not fully clear how this process was orchestrated at the cellular and molecular level, and the current study from Yin et al (2022) advances our understanding, uncovering a previously unknown involvement of endothelial cells (ECs), instructed by the senescent cells, to aid in senescence surveillance.…”

Cellular senescence-related gene signature as a valuable predictor of prognosis in hepatocellular carcinoma

“…And HCC patients with worse clinical outcome had higher immune infiltration than low-risk patients. Tumorigenesis occurs via evading autoimmune-mediated elimination triggered by senescent cells’ senescence-associated secretory phenotype [ 58 ]. CD4 + T cells are resistant to age-related phenotypic and functional changes, and a gradual increase in the percentage of senescent-like CD4 + T lymphocytes is generally seen when an individual ages [ 59 ].…”

Identification and Development of an Age-Related Classification and Signature to Predict Prognosis and Immune Landscape in Osteosarcoma

“…Cellular senescence is an inherent process that inhibits tumor progression, contributing to arresting the cells autonomously in the cell cycle and preventing further divisions. This process also causes the removal of these damaged cells by activating the immune system through the SASP, but if the cells evade this fate, it may lead to tumorigenesis [ 34 ]. Emerging evidence showed that several ARGs may be the cause of onset and advancement of cancers due to regulation of the process of aging and cellular senescence by these ARGs and could be used as a target for cancer therapy [ 35 , 36 ].…”