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Updated: Dec 11, 2025
In Vivo Augmentation of Gut-Homing Regulatory T Cell Induction
Published on: January 22, 2020
BxPC-3-Derived Small Extracellular Vesicles Induce FOXP3+ Treg through ATM-AMPK-Sirtuins-Mediated FOXOs Nuclear
Tao Shen1, Shengnan Jia1, Guoping Ding1
1Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Abstract:
Immunotherapy 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.
Insights
Pancreatic cancer cell-derived extracellular vesicles suppress T lymphocytes by upregulating immune checkpoints and activating specific signaling pathways, hindering immunotherapy. This research uncovers key mechanisms impacting T cell function in pancreatic ductal adenocarcinoma.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Biology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) immunotherapy is limited by poor immunogenicity.
- Cancer cell-derived small extracellular vesicles (sEVs) are known to impair immune responses.
- The specific impact of PDAC-derived sEVs on T lymphocytes remains largely unknown.
Purpose of the Study:
- To investigate the phenotypic and signaling pathway alterations in T lymphocytes exposed to PDAC-derived sEVs.
- To elucidate the mechanisms by which sEVs affect T lymphocyte function.
Main Methods:
- T lymphocytes were treated with sEVs derived from pancreatic cancer cells.
- Mass cytometry (CyTOF) was employed to analyze T lymphocyte phenotypes.
- Gene set enrichment analysis (GSEA) was performed to identify involved pathways.
- Key signaling molecules and transcription factors were assessed.
Main Results:
- sEV-treated T lymphocytes exhibited overexpression of immune checkpoint proteins (PD-1, PD-L1, CTLA4, Tim-3).
- An enrichment of FOXP3+ regulatory T cells (Tregs) was observed in sEV-treated T lymphocytes.
- GSEA suggested involvement of DNA damage response and metabolic pathways in sEV-induced Tregs.
- Sequential activation of ATM, AMPK, SIRT1, SIRT2, and SIRT6 was identified, crucial for upregulating FOXO1A, FOXO3A, and FOXP3.
Conclusions:
- PDAC-derived sEVs significantly impact T lymphocyte function, promoting an immunosuppressive phenotype.
- The study reveals a novel mechanism involving specific signaling pathways (ATM, AMPK, Sirts) and transcription factors (FOXO family) in sEV-mediated T cell modulation.
- These findings offer critical insights for developing novel immunotherapy strategies for PDAC.
