Senescent CD8 T effector memory cells are functionally impaired, enriched in aging and disease, and a barrier to immunotherapy

Senescent cells play important roles in various biological processes that promote fitness and health; however, their timely elimination by immune cells is critical to maintain tissue homeostasis and prevent disease. Despite this, senescent cells accumulate systemically with age, suggesting that certain immune cells also become senescent and dysfunctional during aging. In support of this, we previously demonstrated that CD8 T cells, immune cells capable of targeting senescent cells, increasingly develop characteristics of senescence with advancing age in humans. Here, we characterized the senescence state of human SA-βGal-expressing (SA-βGal ^high ) CD8 T effector memory (EM) cells, their functional capabilities, and their enrichment in aging and disease. Single-cell RNA sequencing revealed that SA-βGal ^high CD8 T cells with unique transcriptional signatures develop in all stages of T cell differentiation, including in CD8 T _EM cells, which increased in abundance with human aging. SA-βGal ^high CD8 T _EM cells expressed various classical markers of senescence and were significantly impaired in their ability to proliferate, produce cytokines, and eliminate senescent human stromal cells. Gene signatures of senescent SA-βGal ^high CD8 T _EM cells were enriched in CD8 T cells from older human donors, patients with age-related disorders, cancer, and in smokers. Furthermore, we show that T cell senescence is distinct from and dominant over T cell exhaustion, limiting the response of CD8 T _EM cells to immune checkpoint blockade. Collectively, our study demonstrates that senescence impairs CD8 T _EM cell function and reveals the involvement of senescent and dysfunctional CD8 T _EM cells in aging, disease, smoking, and responses to immunotherapy.