Cellular senescence: Immunosurveillance and future immunotherapy

Abstract

In response to persistent DNA damage, induction into cell senescence promotes an immunogenic program which facilitates immune clearance of these damaged cells. Under physiological conditions, senescent cells can activate both innate and adaptive immune responses, functioning to maintain tissue homeostasis. In addition, emerging findings suggest that programmed induction of cell senescence may be important for regulating reproductive processes, partly facilitated by immune clearance. However, likely owing to ageing of the immune system, a failure to eliminate senescent cells can contribute to their persistence in tissues, leading to the development and progression of age-related diseases. Such immune failure may in part be due to activation of the senescence program in immune cells, leading to their dysfunction. Furthermore, senescent cells under certain biological contexts have been shown to instead promote immune suppression, a response that may reflect differences between an acute verses chronic senescent phenotype. In this review, we provide an overview of the research to date concerning senescence immunosurviellance, including a focused discussion on the mechanisms by which macrophages may recognise senescent cells. Senescence immunotherapy strategies as an alternative to senolytics for the removal of senescent cells will also be discussed.

To Cycle or Fight—CDK4/6 Inhibitors at the Crossroads of Anticancer Immunity

“…Senescent cells secrete a collection of inflammatory cytokines, chemokines, and proteinases, collectively referred to as the senescence-associated secretory phenotype (SASP) which recruits and activates distinct cells from the innate and adaptive immune system, such as macrophages and natural killer cells as well as T cells (58,59). The SASP is one of the most profound features of senescence with the triggering of immune cell recruitment into the tumor (60,61), although on the other hand, there are concerns that the inflammatory environment chronically stimulated by SASP could be protumorigenic (58).…”

A Multidimensional Systems Biology Analysis of Cellular Senescence in Ageing and Disease

“…Additionally, acute premature senescence can occur as an antagonistic consequence of genomic, epigenomic, or proteomic damage, driven by oncogenic factors, oxidative stress, or radiation (de Magalhaes and Passos, 2018). Initially assumed to be mainly an evolutionary response to reduce mutation accrual and subsequent tumorigenesis, the pleiotropic nature of senescence has since also been positively implicated in embryogenesis (Munoz-Espin et al, 2013;Storer et al, 2013), wound healing (Demaria et al, 2014) and immune clearance (Burton and Stolzing, 2018;Kang et al, 2011). By contrast, the gradual accumulation and chronic persistence of senescent cells with time promotes deleterious effects that are considered to accelerate deterioration and hyperplasia in ageing (Campisi, 2013).…”

Exploring the Relevance of Senotherapeutics for the Current SARS-CoV-2 Emergency and Similar Future Global Health Threats

“…However, the SASP appears to be beneficial or deleterious, depending on the biological context. For example, the SASP is also responsible for activating an immune surveillance response to remove senescent cells [35]. This response seems to involve macrophages, T-cells as well as NK-cells, and appears to differ in different tissues.…”

“…Regarding this last aspect, T-cells engineered to express the NKG2D chimeric antigen receptor (CAR), which recognizes NKG2D ligands on the surface of SCs, may be used to target senescent cells [16,35]. In turn, the recent discovery of dipeptidyl peptidase 4 (DPP4) as a selective membrane marker of cellular senescence may provide a target for the development of immune-mediated clearance of senescent cells [16,93].…”