摘要：SummaryImmunotherapy in pancreatic ductal adenocarcinoma (PDAC) treatment faces serious challenges, due particularly to the poor immunogenicity. Cancer cell-derived small extracellular vesicles (sEVs) play important roles in damaging the immune system. However, the effects of pancreatic cancer-derived sEVs on T lymphocytes are unknown. Here we investigated changes in phenotypes and signal transduction pathways in sEVs-treated T lymphocytes. We identified the overexpression of immune checkpoint proteins PD-1, PD-L1, CTLA4, and Tim-3 and the enrichment of FOXP3+ Treg cluster in sEVs-treated T lymphocytes by CyTOF. Gene set enrichment analysis revealed that DNA damage response and metabolic pathways might be involved in sEVs-induced Tregs. ATM, AMPK, SIRT1, SIRT2, and SIRT6 were activated sequentially in sEVs-treated T lymphocytes and essential for sEVs-upregulated expressions of FOXO1A, FOXO3A, and FOXP3. Our study reveals the impact and mechanism of pancreatic cancer cell-derived sEVs on T lymphocytes and may provide insights into developing immunotherapy strategies for PDAC treatment.Graphical AbstractDisplay OmittedHighlights•Human pancreatic cancer cells-derived sEVs induce Treg promotion•DNA damage responses and metabolism are altered in sEVs-stimulated T lymphocytes•ATM-AMPK-SIRT1/2/6-FOXO1A/3A axis plays a role in sEVs-induced Treg•FOXO1A, FOXO3A, and FOXP3 are highly expressed in pancreatic cancer-involved lymph nodesTherapy; Immunology; Cancer
