Senescent CD8⁺ T cells acquire NK cell-like innate functions to promote antitumor immunity

It has been suggested that aging of the immune system (immunosenescence) results in a decline in the acquired immune response, which is associated with an increase in age-related tumorigenesis. T-cell senescence plays a critical role in immunosenescence and is involved in the age-related decline of the immune function, which increases susceptibility to certain cancers. However, it has been shown that CD8⁺ T cells with the senescent T-cell phenotype acquire an natural killer (NK) cell-like function and are involved in tumor elimination. Therefore, the role of senescent CD8⁺ T cells in tumor immunity remains to be elucidated. In this study, we investigated the role of senescent CD8⁺ T cells in tumor immunity. In a murine model of transferred with B16 melanoma, lung metastasis was significantly suppressed in aged mice (age ≥30 weeks) in comparison to young mice (age 6-10 weeks). We evaluated the cytotoxic activity of CD8⁺ T cells in vitro and found that CD8⁺ T cells from aged mice activated in vitro exhibited increased cytotoxic activity in comparison to those from young mice. We used Menin-deficient effector T cells as a model for senescent CD8⁺ T cells and found that cytotoxic activity and the expression of NK receptors were upregulated in Menin-deficient senescent CD8⁺ T cells. Furthermore, Menin-deficient CD8⁺ T cells can eliminate tumor cells in an antigen-independent manner. These results suggest that senescent effector CD8⁺ T cells may contribute to tumor immunity in the elderly by acquiring NK-like innate immune functions, such as antigen-independent cytotoxic activity.