Department of Urologye, Graduate School of Medicin, Ehime University, Toon, Japan.
Department of Immunology, Graduate School of Medicine, Ehime University, Toon, Japan.
Cancer Sci. 2023 Jul;114(7):2810-2820. doi: 10.1111/cas.15824. Epub 2023 Apr 25.
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.
有人提出，免疫系统的衰老（免疫衰老）导致获得性免疫反应下降，这与年龄相关的肿瘤发生增加有关。T 细胞衰老在免疫衰老中起着关键作用，并参与免疫功能的年龄相关下降，从而增加了某些癌症的易感性。然而，已经表明，具有衰老 T 细胞表型的 CD8 T 细胞获得了自然杀伤（NK）细胞样功能，并参与肿瘤的消除。因此，衰老的 CD8 T 细胞在肿瘤免疫中的作用仍有待阐明。在这项研究中，我们研究了衰老的 CD8 T 细胞在肿瘤免疫中的作用。在转移 B16 黑色素瘤的小鼠模型中，与年轻小鼠（6-10 周龄）相比，老年小鼠（≥30 周龄）的肺部转移明显受到抑制。我们在体外评估了 CD8 T 细胞的细胞毒性活性，发现与年轻小鼠相比，老年小鼠体外激活的 CD8 T 细胞表现出增强的细胞毒性活性。我们使用 Menin 缺陷效应 T 细胞作为衰老的 CD8 T 细胞模型，发现 Menin 缺陷衰老的 CD8 T 细胞中 NK 受体的表达和细胞毒性活性上调。此外，Menin 缺陷的 CD8 T 细胞可以以抗原非依赖性的方式消除肿瘤细胞。这些结果表明，衰老的效应 CD8 T 细胞可能通过获得 NK 样先天免疫功能（如抗原非依赖性细胞毒性活性），在老年人中促进肿瘤免疫。
