Senolytic CAR T cells reverse senescence-associated pathologies

Abstract

Cellular senescence is characterized by stable cell cycle arrest and a secretory program that modulates the tissue microenvironment 1 , 2 . Physiologically, senescence serves as a tumor suppressive mechanism that prevents the expansion of premalignant cells 3 , 4 and plays a beneficial role in wound healing responses 5 , 6 . Pathologically, the aberrant accumulation of senescent cells generates an inflammatory milieu that leads to chronic tissue damage and contributes to diseases such as liver and lung fibrosis, atherosclerosis, diabetes, and osteoarthritis 1 , 7 . Accordingly, elimination of senescent cells from damaged tissues in mice ameliorates symptoms of these pathologies and even promotes longevity 1 , 2 , 8 – 10 . Here we test the therapeutic concept that chimeric antigen receptor (CAR) T cells targeting senescent cells can be effective senolytics. We identify the urokinase plasminogen activator receptor (uPAR) 11 as a cell surface protein broadly induced during senescence and demonstrate that uPAR-specific CAR T cells efficiently ablate senescent cells in vitro and in vivo . uPAR-directed CAR T cells extend the survival of mice harboring lung adenocarcinoma treated with a senescence-inducing drug combination, and restore tissue homeostasis in chemical- or diet-induced liver fibrosis. These results establish the therapeutic potential of senolytic CAR T cells for senescence-associated diseases.

Senolytic chimeric antigen receptor (CAR) T cell: driving the immune system to fight cell senescence

“…In a recent work published in Nature , Amor et al . developed for the first time a senolytic chimeric antigen receptor (CAR) T cell, a breakthrough in the senolytics field 1 . Here, we discuss the study’s main findings and provide insights into future implications.…”

“…The idea of directing a cytotoxic T cell against senescent cells was extremely attractive, but until recently, there was no common biological marker to differentiate senescent from normal cells. In June 2020, a group from Memorial Sloan Kettering Center led by Drs Michel Sadelain and Scott Lowe were able to develop senolytic CAR‐T cells (Figure 1) and revealed their potential against multiple senescence‐associated diseases 1 …”

“…To identify this molecule, the authors analyzed the expression profiles of three different senescence models: therapy‐induced senescence, in which tumor cells are treated with CDK4/6 inhibitors to induce cell cycle arrest; oncogene‐induced senescence, triggered by NRAS G12V expression and replicative senesce. The authors show that uPAR is highly expressed in senescent cells from mouse models and human tissue, but overall absent or present in very low levels in normal cells 1 . This specificity is crucial to avoid off‐target cytotoxic effects.…”

Identification of a Proteomic Signature of Senescence in Primary Human Mammary Epithelial Cells

“…Since the identification of dasatinib and quercetin as the first senolytic drugs (Zhu et al 2015), rapid progress has been made in identification of other senolytic drugs including HSP90 inhibitors (Fuhrmann-Stroissnigg et al 2017), the BCL-2 / BCL-xL inhibitor navitoclax (Zhu et al 2016;Chang et al 2016), the naturally-occurring flavonoid polyphenol fisetin (Yousefzadeh et al 2018), FOXO4-p53 interfering peptides (Baar et al 2017), and others. Cell-based therapies including chimeric antigen receptor (CAR)expressing T cells that recognize senescent cells have also shown great promise as senolytic agents (Amor et al 2020). Importantly, however, senolytic compounds vary by cell type.…”

“…One limitation to the therapeutic targeting of senescent cells has been the lack of robust senescence biomarkers. The identification of cell type-specific senescence biomarkers is particularly essential for therapeutic approaches such as CAR-T cells or drug-loaded nanoparticles that kill senescent cells on the basis of molecular recognition (Amor et al 2020;Muñoz-Espín et al 2018). Liquid chromatography-mass spectrometry (LC-MS) proteomics offers the potential for unbiased, quantitative profiling of biological systems at the protein level (Aebersold & Mann 2016).…”