Towards Senolytic Immunotherapies that Use Cytotoxic T Cells
As researchers here point out, cytotoxic T cells can in principle attack and destroy lingering senescent cells in aged tissues. That they don't do enough of this in old age is clear, but that they are capable of it at all opens the door to finding ways to encourage greater activity. Deciduous Therapeutics runs a development program focused on encouraging a different set of immune cells to kill senescent cells, while engineered T cells equipped with chimeric antigen receptors have been tested in animal models for their ability to kill senescent cells. It is likely that other groups will try a variety of senolytic immunotherapy approaches in the years ahead.
With their continuous production of the senescence-associated secretory phenotype (SASP), senescent cells (SnCs) hinder tissue renewal and accelerate pathological deterioration, thus damaging the development and maintenance of functional ability, which is the major concern of healthy aging. The immune system primarily takes the responsibility of identifying and recycling irregular cells, thus ensuring an endogenous approach to achieve healthy aging. However, the immunosurveillance function gradually loses its balance with cellular and microenvironmental changes in the aging process, indulging the irreversible aging process. Hence, the restoration and mobilization of immunosurveillance could be an entry point to boost healthy aging.
Cytotoxic T lymphocytes (CTLs), as an important part of the immune system, mainly include CD4+ CTLs, CD8+ CTLs, and artificially modified cytotoxic chimeric antigen receptor T cells (CAR T cells). CTLs bind with antigen-presenting target cells, releasing perforin and granzyme which induce the death of target cells. Studies have suggested the well-established role of CTLs in eliminating cancer cells selectively. Could this theory be applied to the elimination of SnCs effectively? p21, a classical marker of cellular senescence, was found to induce CXCL14 and other immune-modulatory factors expression in hepatocytes. These immune modulatory factors further boosted M1 macrophage differentiation and the recruitment of CTLs to p21-expressing hepatocytes, strongly suggesting that CTLs may contribute to the immune clearance of SnCs
Immunosurveillance on aging is a complex yet poorly understood natural process. Revealing attempts have been made to identify prominent senescent hallmarks that activate CTLs. Furthermore, the demonstration of how SnCs are eliminated by CTLs in natural processes offers potential interference approaches. The exploratory application of immune checkpoint blockade and CAR T cells provides strategies to prevent SnCs from escaping immunosurveillance. With the discovery of new aging hallmarks and successful mobilization of CTLs, future senolysis may contribute to healthy aging and prevent aging-related diseases.