Abstract P119: Senescent Cell-Derived Extracellular Vesicles Distinctly Impede Tumor Recurrence by Antitumor Immune Response and Function

Abstract

Triple-negative breast cancers (TNBC), associated with poor prognosis and high tumour recurrence, are often-treated with taxanes in first-line treatment regimens. However, acquired disease resistance can often set in, hampering clinical efficacy. Senescent cells represent a population of residual disease that are highly secretory and drive cancer relapse. Although it is known that therapy-induced senescence (TIS) can contribute to tumour development and therapy resistance via the therapy-induced secretome, the underlying cellular and molecular mechanisms are not fully understood. Here, we show that paclitaxel-treated TNBCs induced mitotic slippage and the tetraploid cells entered senescence. The therapy-induced SASP was found to be enriched in soluble cytokines and other pro-tumorigenic factors linked to tumor recurrence and distant metastasis. Interestingly, we uncovered a striking phenotype where senescence-associated small extracellular vesicles (sEVs), an underappreciated component of SASP, increases genomic instability (DNA damage, micronuclei) and paracrine senescence. Unlike soluble SASP factors, TIS-sEVs reduced migration and invasion unlike sEVs from proliferating cells. Additionally, TIS-sEV elicited a strong immune response leading to tumor regression in mice. This study hence revealed an unexpected role for sEVs where enriched TIS sEVs can function as discrete SASP entities with anti-tumourigenic properties.