Senescent cell extracellular vesicles are critical elements restricting cancer recurrence [bulk RNA-seq]

Senescent cell extracellular vesicles (senEVs)are novel and underappreciated components of the senescence secretome. To understand the role that senEVs play in inflammatory responses to senescence, we developed and validated a novel engraftment-based senescence model that allowed us to genetically block the release of senEVs in vivo. We found that senEVs orchestrate prompt removal of senescent cells and inhibit tumor recurrence. Recruitment of MHC-II+ antigen presenting cells into the senescence microenvironment was significantly decreased in the absence of senEVs. Inhibition of senEV release changed the primary target of senescent cell signaling from antigen presenting cells to neutrophils. Antigen presenting cells recruited and activated CCR2+ TH17 cells, which in turn inhibited B cell activation. Through multimodal transcriptional and proteomic analysis, we identified 6 ligands that were specific to senEVs, suggesting a role in promoting cell adhesion. Overall, these results indicate that senEVs complement the activity of secreted inflammatory mediators in recruiting and activating distinct immune cell subsets for efficient removal of senescent cells.