Irreversible electroporation reverses resistance to immune checkpoint blockade in pancreatic cancer

Jun Zhao; Xiaofei Wen; Li Tian; Tingting Li; Chunyu Xu; Xiaoxia Wen; Marites P. Melancon; Sanjay Gupta; Baozhong Shen; Weiyi Peng; Chun Li

doi:10.1038/s41467-019-08782-1

Irreversible electroporation reverses resistance to immune checkpoint blockade in pancreatic cancer

Jun Zhao, Xiaofei Wen, Li Tian, Tingting Li, Chunyu Xu, Xiaoxia Wen, Marites P. Melancon, Sanjay Gupta, Baozhong Shen, Weiyi Peng, Chun Li

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169 Scopus citations

Abstract

Immunotherapy has only limited efficacy against pancreatic ductal adenocarcinoma (PDAC) due to the presence of an immunosuppressive tumor-associated stroma. Here, we demonstrate an effective modulation of that stroma by irreversible electroporation (IRE), a local ablation technique that has received regulatory approval in the United States. IRE induces immunogenic cell death, activates dendritic cells, and alleviates stroma-induced immunosuppression without depleting tumor-restraining collagen. The combination of IRE and anti-programmed cell death protein 1 (anti-PD1) immune checkpoint blockade promotes selective tumor infiltration by CD8 ⁺ T cells and significantly prolongs survival in a murine orthotopic PDAC model with a long-term memory immune response. Our results suggest that IRE is a promising approach to potentiate the efficacy of immune checkpoint blockade in PDAC.

Original language	English (US)
Article number	899
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-08782-1
State	Published - Dec 1 2019

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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title = "Irreversible electroporation reverses resistance to immune checkpoint blockade in pancreatic cancer",

abstract = " Immunotherapy has only limited efficacy against pancreatic ductal adenocarcinoma (PDAC) due to the presence of an immunosuppressive tumor-associated stroma. Here, we demonstrate an effective modulation of that stroma by irreversible electroporation (IRE), a local ablation technique that has received regulatory approval in the United States. IRE induces immunogenic cell death, activates dendritic cells, and alleviates stroma-induced immunosuppression without depleting tumor-restraining collagen. The combination of IRE and anti-programmed cell death protein 1 (anti-PD1) immune checkpoint blockade promotes selective tumor infiltration by CD8 + T cells and significantly prolongs survival in a murine orthotopic PDAC model with a long-term memory immune response. Our results suggest that IRE is a promising approach to potentiate the efficacy of immune checkpoint blockade in PDAC.",

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AU - Zhao, Jun

AU - Wen, Xiaofei

AU - Tian, Li

AU - Li, Tingting

AU - Xu, Chunyu

AU - Wen, Xiaoxia

AU - Melancon, Marites P.

AU - Gupta, Sanjay

AU - Shen, Baozhong

AU - Peng, Weiyi

AU - Li, Chun

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Immunotherapy has only limited efficacy against pancreatic ductal adenocarcinoma (PDAC) due to the presence of an immunosuppressive tumor-associated stroma. Here, we demonstrate an effective modulation of that stroma by irreversible electroporation (IRE), a local ablation technique that has received regulatory approval in the United States. IRE induces immunogenic cell death, activates dendritic cells, and alleviates stroma-induced immunosuppression without depleting tumor-restraining collagen. The combination of IRE and anti-programmed cell death protein 1 (anti-PD1) immune checkpoint blockade promotes selective tumor infiltration by CD8 + T cells and significantly prolongs survival in a murine orthotopic PDAC model with a long-term memory immune response. Our results suggest that IRE is a promising approach to potentiate the efficacy of immune checkpoint blockade in PDAC.

AB - Immunotherapy has only limited efficacy against pancreatic ductal adenocarcinoma (PDAC) due to the presence of an immunosuppressive tumor-associated stroma. Here, we demonstrate an effective modulation of that stroma by irreversible electroporation (IRE), a local ablation technique that has received regulatory approval in the United States. IRE induces immunogenic cell death, activates dendritic cells, and alleviates stroma-induced immunosuppression without depleting tumor-restraining collagen. The combination of IRE and anti-programmed cell death protein 1 (anti-PD1) immune checkpoint blockade promotes selective tumor infiltration by CD8 + T cells and significantly prolongs survival in a murine orthotopic PDAC model with a long-term memory immune response. Our results suggest that IRE is a promising approach to potentiate the efficacy of immune checkpoint blockade in PDAC.

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Irreversible electroporation reverses resistance to immune checkpoint blockade in pancreatic cancer

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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