Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden.
Centre de Recherche des Cordeliers, Equipe Labellisé Par La Ligue Contre le Cancer, Université Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France; Institut Du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
Biomed J. 2023 Jun;46(3):100581. doi: 10.1016/j.bj.2023.02.001. Epub 2023 Feb 4.
Cellular senescence is a complex process involving a close-to-irreversible arrest of the cell cycle, the acquisition of the senescence-associated secretory phenotype (SASP), as well as profound changes in the expression of cell surface proteins that determine the recognition of senescent cells by innate and cognate immune effectors including macrophages, NK, NKT and T cells. It is important to note that senescence can occur in a transient fashion to improve the homeostatic response of tissues to stress. Moreover, both the excessive generation and the insufficient elimination of senescent cells may contribute to pathological aging. Attempts are being made to identify the mechanisms through which senescent cell avoid their destruction by immune effectors. Such mechanisms involve the cell surface expression of immunosuppressive molecules including PD-L1 and PD-L2 to ligate PD-1 on T cells, as well as tolerogenic MHC class-I variants. In addition, senescent cells can secrete factors that attract immunosuppressive and pro-inflammatory cells into the microenvironment. Each of these immune evasion mechanism offers a target for therapeutic intervention, e.g., by blocking the interaction between PD-1 and PD-L1 or PD-L2, upregulating immunogenic MHC class-I molecules and eliminating immunosuppressive cell types. In addition, senescent cells differ in their antigenic makeup and immunopeptidome from their normal counterparts, hence offering the opportunity to stimulate immune response against senescence-associated antigens. Ideally, immunological anti-senescence strategies should succeed in selectively eliminating pathogenic senescent cells but spare homeostatic senescence.
细胞衰老（Cellular senescence）是一个复杂的过程，涉及到细胞周期的近乎不可逆的停滞，获得衰老相关的分泌表型（SASP），以及细胞表面蛋白表达的深刻变化，这些变化决定了固有和同源免疫效应器（包括巨噬细胞、NK、NKT 和 T 细胞）对衰老细胞的识别。需要注意的是，衰老可以暂时发生，以改善组织对压力的稳态反应。此外，衰老细胞的过度产生和不足的消除都可能导致病理性衰老。人们正在努力识别衰老细胞避免被免疫效应器破坏的机制。这些机制涉及到免疫抑制分子的细胞表面表达，包括 PD-L1 和 PD-L2，它们与 T 细胞上的 PD-1 结合，以及耐受型 MHC 类-I 变体。此外，衰老细胞可以分泌吸引免疫抑制和促炎细胞进入微环境的因子。这些免疫逃避机制中的每一种都为治疗干预提供了一个靶点，例如，通过阻断 PD-1 与 PD-L1 或 PD-L2 的相互作用，上调免疫原性 MHC 类-I 分子，以及消除免疫抑制细胞类型。此外，衰老细胞在其抗原组成和免疫肽组上与正常细胞不同，因此有机会刺激针对衰老相关抗原的免疫反应。理想情况下，免疫性抗衰老策略应该能够选择性地消除致病性衰老细胞，但不影响稳态衰老细胞。
