Nano-enabled pancreas cancer immunotherapy using immunogenic cell death and reversing immunosuppression

Jianqin Lu; Xiangsheng Liu; Yu Pei Liao; Felix Salazar; Bingbing Sun; Wen Jiang; Chong Hyun Chang; Jinhong Jiang; Xiang Wang; Anna M. Wu; Huan Meng; Andre E. Nel

doi:10.1038/s41467-017-01651-9

Nano-enabled pancreas cancer immunotherapy using immunogenic cell death and reversing immunosuppression

Jianqin Lu, Xiangsheng Liu, Yu Pei Liao, Felix Salazar, Bingbing Sun, Wen Jiang, Chong Hyun Chang, Jinhong Jiang, Xiang Wang, Anna M. Wu, Huan Meng, Andre E. Nel

Research output: Contribution to journal › Article › peer-review

241 Scopus citations

Abstract

While chemotherapy delivery by nanocarriers has modestly improved the survival prospects of pancreatic ductal adenocarcinoma (PDAC), additional engagement of the immune response could be game changing. We demonstrate a nano-enabled approach for accomplishing robust anti-PDAC immunity in syngeneic mice through the induction of immunogenic cell death (ICD) as well as interfering in the immunosuppressive indoleamine 2,3-dioxygenase (IDO) pathway. This is accomplished by conjugating the IDO inhibitor, indoximod (IND), to a phospholipid that allows prodrug self-Assembly into nanovesicles or incorporation into a lipid bilayer that encapsulates mesoporous silica nanoparticles (MSNP). The porous MSNP interior allows contemporaneous delivery of the ICD-inducing chemotherapeutic agent, oxaliplatin (OX). The nanovesicles plus free OX or OX/IND-MSNP induce effective innate and adaptive anti-PDAC immunity when used in a vaccination approach, direct tumor injection or intravenous biodistribution to an orthotopic PDAC site. Significant tumor reduction or eradication is accomplishable by recruiting cytotoxic T lymphocytes, concomitant with downregulation of Foxp3⁺ T cells.

Original language	English (US)
Article number	1811
Journal	Nature communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-01651-9
State	Published - Dec 1 2017
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/s41467-017-01651-9

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Nano-enabled pancreas cancer immunotherapy using immunogenic cell death and reversing immunosuppression. / Lu, Jianqin; Liu, Xiangsheng; Liao, Yu Pei; Salazar, Felix; Sun, Bingbing; Jiang, Wen; Chang, Chong Hyun; Jiang, Jinhong; Wang, Xiang; Wu, Anna M.; Meng, Huan; Nel, Andre E.

In: Nature communications, Vol. 8, No. 1, 1811, 01.12.2017.

Research output: Contribution to journal › Article › peer-review

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title = "Nano-enabled pancreas cancer immunotherapy using immunogenic cell death and reversing immunosuppression",

abstract = "While chemotherapy delivery by nanocarriers has modestly improved the survival prospects of pancreatic ductal adenocarcinoma (PDAC), additional engagement of the immune response could be game changing. We demonstrate a nano-enabled approach for accomplishing robust anti-PDAC immunity in syngeneic mice through the induction of immunogenic cell death (ICD) as well as interfering in the immunosuppressive indoleamine 2,3-dioxygenase (IDO) pathway. This is accomplished by conjugating the IDO inhibitor, indoximod (IND), to a phospholipid that allows prodrug self-Assembly into nanovesicles or incorporation into a lipid bilayer that encapsulates mesoporous silica nanoparticles (MSNP). The porous MSNP interior allows contemporaneous delivery of the ICD-inducing chemotherapeutic agent, oxaliplatin (OX). The nanovesicles plus free OX or OX/IND-MSNP induce effective innate and adaptive anti-PDAC immunity when used in a vaccination approach, direct tumor injection or intravenous biodistribution to an orthotopic PDAC site. Significant tumor reduction or eradication is accomplishable by recruiting cytotoxic T lymphocytes, concomitant with downregulation of Foxp3+ T cells.",

author = "Jianqin Lu and Xiangsheng Liu and Liao, {Yu Pei} and Felix Salazar and Bingbing Sun and Wen Jiang and Chang, {Chong Hyun} and Jinhong Jiang and Xiang Wang and Wu, {Anna M.} and Huan Meng and Nel, {Andre E.}",

note = "Funding Information: This study was funded by the U.S. Public Health Service Grant U01CA198846, and NIH grants R21 CA190044 and P30 CA016042. The authors thank the Molecular Instrumentation Center for NMRs and Mass Spectrometry, the CNSI Advanced Light Microscopy/Spectroscopy Shared Facility for confocal fluorescent microscopy, the use of EM instruments at the Electron Imaging Center for Nanomachines, the IHC staining in the Translational Pathology Core Laboratory (TPCL) at UCLA Jonsson Comprehensive Cancer Center, and the Crump Institute for Molecular Imaging at UCLA. The authors are grateful to Dr. Richard Tavar{\'e} for production and characterization of the anti-CD8 cys-diabody. We also thank Wenting Tsai for assisting with the immuno-PET imaging animal studies, and Teresa Kim Tran for assistance in the in vitro related studies. Publisher Copyright: {\textcopyright} 2017 The Author(s).",

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AU - Lu, Jianqin

AU - Liu, Xiangsheng

AU - Liao, Yu Pei

AU - Salazar, Felix

AU - Sun, Bingbing

AU - Jiang, Wen

AU - Chang, Chong Hyun

AU - Jiang, Jinhong

AU - Wang, Xiang

AU - Wu, Anna M.

AU - Meng, Huan

AU - Nel, Andre E.

N1 - Funding Information: This study was funded by the U.S. Public Health Service Grant U01CA198846, and NIH grants R21 CA190044 and P30 CA016042. The authors thank the Molecular Instrumentation Center for NMRs and Mass Spectrometry, the CNSI Advanced Light Microscopy/Spectroscopy Shared Facility for confocal fluorescent microscopy, the use of EM instruments at the Electron Imaging Center for Nanomachines, the IHC staining in the Translational Pathology Core Laboratory (TPCL) at UCLA Jonsson Comprehensive Cancer Center, and the Crump Institute for Molecular Imaging at UCLA. The authors are grateful to Dr. Richard Tavaré for production and characterization of the anti-CD8 cys-diabody. We also thank Wenting Tsai for assisting with the immuno-PET imaging animal studies, and Teresa Kim Tran for assistance in the in vitro related studies. Publisher Copyright: © 2017 The Author(s).

PY - 2017/12/1

Y1 - 2017/12/1

N2 - While chemotherapy delivery by nanocarriers has modestly improved the survival prospects of pancreatic ductal adenocarcinoma (PDAC), additional engagement of the immune response could be game changing. We demonstrate a nano-enabled approach for accomplishing robust anti-PDAC immunity in syngeneic mice through the induction of immunogenic cell death (ICD) as well as interfering in the immunosuppressive indoleamine 2,3-dioxygenase (IDO) pathway. This is accomplished by conjugating the IDO inhibitor, indoximod (IND), to a phospholipid that allows prodrug self-Assembly into nanovesicles or incorporation into a lipid bilayer that encapsulates mesoporous silica nanoparticles (MSNP). The porous MSNP interior allows contemporaneous delivery of the ICD-inducing chemotherapeutic agent, oxaliplatin (OX). The nanovesicles plus free OX or OX/IND-MSNP induce effective innate and adaptive anti-PDAC immunity when used in a vaccination approach, direct tumor injection or intravenous biodistribution to an orthotopic PDAC site. Significant tumor reduction or eradication is accomplishable by recruiting cytotoxic T lymphocytes, concomitant with downregulation of Foxp3+ T cells.

AB - While chemotherapy delivery by nanocarriers has modestly improved the survival prospects of pancreatic ductal adenocarcinoma (PDAC), additional engagement of the immune response could be game changing. We demonstrate a nano-enabled approach for accomplishing robust anti-PDAC immunity in syngeneic mice through the induction of immunogenic cell death (ICD) as well as interfering in the immunosuppressive indoleamine 2,3-dioxygenase (IDO) pathway. This is accomplished by conjugating the IDO inhibitor, indoximod (IND), to a phospholipid that allows prodrug self-Assembly into nanovesicles or incorporation into a lipid bilayer that encapsulates mesoporous silica nanoparticles (MSNP). The porous MSNP interior allows contemporaneous delivery of the ICD-inducing chemotherapeutic agent, oxaliplatin (OX). The nanovesicles plus free OX or OX/IND-MSNP induce effective innate and adaptive anti-PDAC immunity when used in a vaccination approach, direct tumor injection or intravenous biodistribution to an orthotopic PDAC site. Significant tumor reduction or eradication is accomplishable by recruiting cytotoxic T lymphocytes, concomitant with downregulation of Foxp3+ T cells.

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Nano-enabled pancreas cancer immunotherapy using immunogenic cell death and reversing immunosuppression

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