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Final Report Summary - SENESCENCE CLEARANCE (Mechanisms of immune surveillance of senescent cells)

Cellular senescence is a stable form of proliferative arrest that acts as a potent barrier to cancer development and may contribute to various age-related pathologies. The senescence program is controlled by interplay between the Rb and p53 tumor suppressor networks, and DNA damage response. Senescent cells typically display a characteristic transcriptional profile involving downregulation of growth promoting genes, upregulation of cell cycle inhibitors, and changes in the expression of secreted molecules involved in extracellular matrix production and immune surveillance. Although senescent cells can remain viable in culture indefinitely, their fate in tissue is not well characterized. On one hand, benign melanocytic nevi (moles) are highly enriched for senescent cells yet can exist in skin throughout a lifetime, implying that senescent cells can be stably incorporated into tissue. On the other hand, liver carcinoma cells induced to undergo senescence in vivo can be cleared by components of the innate immune system leading to tumor regression. Therefore, senescent cells can turn over in vivo. It is conceivable that senescent cells derived from different cell population e.g. epithelial cells vs. mesenchymal cells present different properties contributing to their differential recognition by the immune system. From the other side decline in the immune function associated with age or diseases of the immune system can contribute to accumulation of senescent cells. Therefore it is important to understand how senescent cells are eliminated from tissues.
The presence of senescent cells in tissues might affect the microenvironment by secretion of cytokines and chemokines as well as direct interaction with the immune cells to modulate disease progression and tissue repair. Indeed, in groundbreaking studies we have demonstrated that the clearance of senescent cells by the innate immune system plays a role in tumour regression following p53 reactivation and establishment of senescence in liver carcinomas in situ. Moreover, in liver fibrosis, the precursor pathology for cirrhosis, I have shown that the main fibrogenic cell type in the liver, activated hepatic stellate cells, become senescent and are cleared by the NK cells thus limiting fibrosis progression and facilitating its reversion. Similar mechanisms were also shown to contribute to the outcome of chemotherapy for certain malignancies. The mechanisms whereby immune cells recognize and clear senescent cells are not understood. We aim to identify molecular players that enable NK cells and macrophages to target senescent cells.
NK cells recognize their target cells using activating and inhibitory receptors. In this work we identified ligands for the NK cell activating receptor that are upregulated on senescent cells. We show that these ligands and their receptor are important for the recognition of senescent cells by NK cells. We also verified our findings in vivo using a knockout mice mouse model. We also studied the regulation of the expression of the ligands in senescent cells. Our results reveal mechanisms of the preferential recognition of senescent cell by NK cells in vitro and in vivo.
Following the recognition of senescent cells, NK cell eliminate senescent cells from tissues. NK cells use two mechanisms to eliminate their target cells: granule exocytosis and death receptor ligands. We show that granule exocytosis, but not death receptor-mediated apoptosis, is required for NK cell-mediated killing of senescent cells. This pathway bias is due to upregulation of the decoy death receptor, Dcr2, an established senescence marker that attenuates NK-mediated cell death. Accordingly, mice with defects in granule exocytosis accumulate senescent stellate cells and display more liver fibrosis in response to a fibrogenic agent. Our results thus provide new insights into the immune surveillance of senescent cells and reveal how granule exocytosis plays a protective role against liver fibrosis.
The interaction of senescent cells with the immune system is not limited to NK cells. We have studied the interaction of macrophages, another component of the innate immune system, with senescent cells. We have shown that senescent cells secrete variety of cytokines that attract macrophages and other immune cells. We have shown that macrophages can recognize and engulf senescent cells in the response to the signals from the senescent cells.
Our experiments shed light on a previously unappreciated mechanism of immune surveillance. This mechanism may limit tumorigenesis and help to restore tissue homeostasis following damage; in doing so it may suggest novel strategies for cancer prevention or tissue repair.

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