The Immunogenicity of Human Senescent Cells Is Dependent on the Senescence Inducer and Cell Type

Senescent cells accumulate with age and after exposure to various stresses, contributing to chronic diseases and cancer, effects largely driven by the senescence-associated secretory phenotype (SASP). Recent evidence indicates that a subset of senescent cells exhibits immunogenic properties. However, the extent to which immunogenicity depends on the cell type and the senescence inducer remains unclear. In this study, we evaluated the immunogenic properties of various human cell types induced to senesce following exposure to ionizing radiation (IR) or oncogenic RAS. Specifically, we used human dermal fibroblasts (HDF) and induced pluripotent stem cell (iPSC)-derived myoblasts (i-MB), endothelial cells (i-EC), lung progenitor cells (i-LPC), along with immune cells from autologous donors. Our results showed that cell types exhibit a distinct SASP and express a variety of inhibitory immune ligands. Notably, senescent HDF displayed a unique immunopeptidome but failed to elicit specific immune responses from CD8+ T cells or NK cells. Similarly, senescent i-EC and i-LPC exhibited limited immunogenicity. In contrast, RAS-induced senescent myoblasts demonstrated immunogenicity, characterized by T cell activation, NK cell-mediated cytotoxicity, and immune cell recruitment in an orthotopic humanized mouse model. These findings highlight the influence of cell type and senescence inducer on immunogenicity and suggest that targeted strategies will be necessary to address the deleterious consequences of the accumulation of distinct senescent cell types.