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

53 Pages Posted: 12 Feb 2020 Publication Status: Review Complete

See all articles by Tao Shen

Tao Shen

Zhejiang University - Department of General Surgery

Shengnan Jia

Zhejiang University - Department of General Surgery

Guoping Ding

Zhejiang University - Department of General Surgery

Dongnan Ping

Zhejiang University - Department of General Surgery

Liangjing Zhou

Zhejiang University - Department of General Surgery

Senhao Zhou

Zhejiang University - Department of General Surgery

Liping Cao

Zhejiang University - Department of General Surgery

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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

Suggested Citation

Shen, Tao and Jia, Shengnan and Ding, Guoping and Ping, Dongnan and Zhou, Liangjing and Zhou, Senhao and Cao, Liping, BxPC-3-Derived Exosomes Induce FOXP3+ Treg Through ATM-AMPK-Sirtuins Mediated FOXOs Nuclear Translocations. Available at SSRN: https://ssrn.com/abstract=3535876 or http://dx.doi.org/10.2139/ssrn.3535876
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Tao Shen

Zhejiang University - Department of General Surgery

Hangzhou, 310016
China

Shengnan Jia

Zhejiang University - Department of General Surgery

Hangzhou, 310016
China

Guoping Ding

Zhejiang University - Department of General Surgery ( email )

Hangzhou, 310016
China

Dongnan Ping

Zhejiang University - Department of General Surgery ( email )

Hangzhou, 310016
China

Liangjing Zhou

Zhejiang University - Department of General Surgery ( email )

Hangzhou, 310016
China

Senhao Zhou

Zhejiang University - Department of General Surgery ( email )

Hangzhou, 310016
China

Liping Cao (Contact Author)

Zhejiang University - Department of General Surgery ( email )

Hangzhou, 310016
China

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