Editors' ChoiceAging

Cellular senolytics

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Science Translational Medicine  01 Jul 2020:
Vol. 12, Issue 550, eabd3075
DOI: 10.1126/scitranslmed.abd3075

Abstract

Repurposing CAR T cells to target senescent cells ameliorates liver fibrosis and extends survival in mice with lung adenocarcinoma.

The accumulation of cells with impairments in replicative ability (cell senescence) promotes various pathologies through both loss of cellular functions and secretion of proinflammatory cytokines. Therapeutic approaches to specifically remove senescent cells (senolytics) from tissue have shown promising results in attenuating various diseases such as osteoarthritis, sarcopenia, and cognition-associated neuronal loss. However, many senolytic modalities, which are based on small molecules, suffer from side effects and lack of potency.

Amor and colleagues repurposed an immunotherapy that was the basis for the 2018 Nobel Prize in Medicine, the chimeric antigen receptor (CAR) T cell, as a senolytic agent. CAR T cells are autologous cells engineered to express specific surface receptors that bind to receptors on cells of interest and selectively induce their destruction. The authors used a bioinformatics approach to identify a unique surface marker on senescent cells, the urokinase-type plasminogen activator receptor (uPAR), and confirmed this marker through a series of mouse senescence models and human patient samples with senescence-associated disorders. Next, the authors developed a uPAR-specific CAR T cell system and showed that the immunotherapy mitigated senescent tumor cells in a lung adenocarcinoma model and also reduced proinflammatory senescent cells that contribute to liver fibrosis.

A critical unknown of this new therapy is the persistence of these effects over time. However, this promising study sets the stage for combinatorial studies, targeting other surface markers as well as generating gene circuits in these cells to activate treatment for adjacent cells.

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