A key hallmark of aging is the accumulation of senescent cells

Senescence is a stress response program whereby damaged cells stop replicating and performing their functions and instead become highly proinflammatory. In physiological conditions senescent cells are eliminated by the immune system.

During aging however, the increase in damaged cells plus the decreased efficiency of the immune system leads to the accumulation of senescent cells in tissues where they generate a chronic proinflammatory milieu that drives age pathologies. In our lab we seek to understand how the immune system targets these cells and to develop immune-based senolytics as therapeutic approaches for age-related diseases including cancer.

Development of senolytic cell therapy

Inspired by the natural role of the immune system in eliminating senescent cells we have developed the first senolytic chimeric antigen receptor T cells (CAR T cells). Our work has shown that senolytic CAR T cells targeting uPAR expression on senescent cells are highly effective at safely eliminating senescent cells in models of fibrosis, cancer and physiological aging.

Unlike other therapeutics, senolytic CAR T cells develop persistence after a single infusion. Our current efforts focus on the optimization of senolytic cellular therapy in terms of target, cell type and CAR designs with the ultimate goal of reaching the clinical development of senolytic cellular therapy in cancer and age-related pathologies.

Elucidating mechanisms of senescence immune surveillance

The composition of the proinflammatory molecules and the surface proteins expressed by senescent cells is highly heterogeneous and context-dependent as are the immune cells that are recruited to target senescent cells in different tissues. Therefore, how immune cells are recruited and recognize senescent cells is currently unclear.

Our lab is interested in understanding the physiologic mechanisms of immune surveillance and how these are derailed in cancer, aging and age-related pathologies. To address these questions our lab is applying a variety of proteomic and immunological approaches coupled to novel somatic mouse models of disease.