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

Abstract

AbstractSenescent cell removal is a promising therapeutic approach to prevent and treat cancer. However, adverse reactions to current senolytic drugs, particularly, in geriatric populations with a compromised immune system and chronic inflammation, highlights a demand for research to develop targeted Immunotherapeutic. Cellular senescence is a cell autonomous tumor suppressor response to stressors that arrests cell cycle and initiates immune-mediated removal of senescent cells. Pathologic processes interfere with immune response leading to persistence of senescent cells and tumor progression. Investigating the communication pathways between senescent and immune cells has the promise of bringing to light therapeutic targets. Recently, it has been shown that senescent cells produce extracellular vesicles (EVs) containing signaling components resemblance to their parental cells. In order to study if and how senescent cell-derived extracellular vesicles (senEVs) contribute to immune-mediated removal of senescent cells, we inhibited EVs using dominant-negative mutant Rab35, while preserving soluble phenotypes. We then challenged C57BL6 mice with EV-inhibited or EV-competent senescent cells and evaluated immune infiltrates. Interfering with EV release led to the reduction of antigen-presenting cells including dendritic cells, macrophages, and B cells, which may contribute to the observed persistence of senescent cells. Interestingly, EV-inhibition reverted cellular senescence, promoted proliferation and tumor formation. Proteomic analysis revealed several proteins that were exclusively present on senEVs, compared to those from their non-senescent counterparts and some common biomarkers were found in two different cell lines. These results suggest that senEVs have a critical role in immune-mediated removal of senescent cells possibly via signaling to immune cells. Further investigations are required to declare common biomarker(s) on senEVs, which specifically are detected by immune cells.