Cells become senescent in response to potentially cancer-inducing stresses and damage, to tissue injury, or when they reach the Hayflick limit on cellular replication. Senescent cells cease to replicate and secrete pro-inflammatory, pro-growth signals. They are cleared by the immune system or via programmed cell death mechanisms. Their presence is beneficial in the short term, an important part of the panoply of mechanisms devoted to, separately, cancer suppression and regeneration. When senescent cells begin to linger, however, their secretions become highly disruptive to normal tissue function. Senescent cell accumulation is an important contributing cause of chronic inflammation, fibrosis, and other forms of age-related disease. Clearing these cells via senolytic treatments produces rapid and sizable rejuvenation in aged animal models.
Cellular senescence in T cells of the adaptive immune system is a fascinating topic, as immune cells come under a very different pattern of replication stress than is the case for the cells types that make up the tissues of the body. Bursts of replication occur as a part of the immune response to pathogens, damage, and so forth. In the case of persistent pathogens this can lead to an ever increasing burden of replication, pushing ever more T cells to the Hayflick limit and senescence, making the immune system both weaker and actively harmful to the individual. Senescent T cells present in the body for the long term are just as problematic, due to their pro-inflammatory secretions, as lingering senescent cells of other cell types. That has implications for many aspects of health, aging, and age-related disease, cancer included.
The exhaustion and senescence of T cells are two dominant dysfunctional states in chronic infections and cancers. The principle features of exhausted T cells is the elevated inhibitory receptors, including PD-1, Tim-3, and LAG-3 with impaired cytotoxicity and effector cytokine production. Senescent T cells have a distinct phenotypes including downregulated expression of the costimulatory molecules CD27 and CD28, and high expression of CD57, KLRG-1, and CD45RA. They share common features with senescent somatic cells such as DNA damage, declines in proliferation and activation, but are able to produce high amounts of proinflammatory cytokines. The dysfunction of exhausted T cells can be reversed by immune checkpoint blockades whereas senescent seems to be irreversible. The exhausted and senescent T cells share overlapping characteristics but they are two distinct dysfunctional states.
The accumulation of senescent T cells was first found in the peripheral blood of elderly people. Therefore, T cell senescence is thought to be attributed to the failing efficacy of vaccination and the increased morbidity and mortality from infections and cancer in ageing. Soon thereafter, an increase in senescent T cells was also detected in young patients with chronic viral infections or autoimmune disorders. This phenomenon indicates that in addition to ageing, repeated antigenic stimulation and a chronic inflammatory environment can also lead to T cell senescence. Considering that T cells may be constitutively activated by antigens and influenced by numerous inflammatory cytokines, the tumour microenvironment may be the origin of senescent T cells.
Increasing evidence suggests a link between T cell senescence and tumour progression. Studies have indicated that the tumour microenvironment promotes the senescence of T cells through multiple pathways. The accumulation of senescent T cells may be responsible for advanced cancer and the low response rate to chemotherapy and radiotherapy, as well as immunotherapy. Thus, preventing and restoring T cell senescence could be novel therapeutic strategies for cancer treatment.