Senescent cell-derived extracellular vesicles recruit antigen presenting cells and limit squamous carcinoma recurrence

Abstract

Extracellular vesicles (EVs) are key signaling mediators. To explore the role of senescent cell-derived extracellular vesicles (senEVs) in inflammatory responses to senescence, we developed an engraftment-based senescence model in wild-type mice and genetically blocked senEV release in vivo, without significantly affecting soluble mediators. Our results demonstrate that senEVs are both necessary and sufficient to trigger immune-mediated clearance of senescent cells, thereby suppressing tumor growth. In the absence of senEVs, the recruitment of MHC-II+ antigen-presenting cells to the senescence microenvironment was markedly impaired. Blocking senEV release redirected the primary target of senescent cell signaling from antigen-presenting cells to neutrophils. Through comprehensive transcriptional and proteomic analyses, we identified six ligands specific to senEVs, highlighting their role in promoting antigen-presenting cell-T cell adhesion and synapse formation. Antigen-presenting cells activated CCR2+CD4+ TH17 cells, which appeared to inhibit B cell activation. CD4 T cells were essential for preventing tumor recurrence, indicating that CCR2+ TH17 cells function downstream of senEVs during senescence surveillance. Our findings suggest that senEVs complement the activity of secreted inflammatory mediators by recruiting and activating distinct immune cell subsets, thereby enhancing the efficient clearance of senescent cells. These conclusions may have implications not only for tumor recurrence but also for understanding senescence during de novo carcinogenesis. Consequently, this work could inform the development of novel cancer early detection strategies based on the biology of cellular senescence.