BxPC-3-Derived Exosomes Induce FOXP3+ Treg Through ATM-AMPK-Sirtuins Mediated FOXOs Nuclear Translocations

Abstract

Immunotherapy in pancreatic ductal adenocarcinoma (PDAC) treatment faces serious challenges, due particularly to the poor immunogenicity of PDAC. Cancer cell-derived exosomes play important roles in damaging the immune system. However, the effects of pancreatic cancer-derived exosomes on T lymphocytes are unknown. Here we investigated changes in phenotypes and signal transduction pathways in exosomes-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 exosomes-treated T lymphocytes by CyTOF. RNA-sequencing and Gene Set Enrichment Analysis revealed that DNA damage response and metabolic pathways might be involved in exosomes-induced Tregs. ATM, AMPK, SIRT1, SIRT2, and SIRT6 were activated sequentially in exosomes-treated T lymphocytes and essential for exosomes-upregulated expressions of FOXO1A, FOXO3A and FOXP3. Our study reveals the impact and mechanism of pancreatic cancer cell-derived exosomes on T lymphocytes and may provide insights into developing immunotherapy strategies for PDAC treatment.

Keywords: Pancreatic cancer, exosomes, Treg, ATM, AMPK, sirtuin