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.

Details

Title
Nano-enabled pancreas cancer immunotherapy using immunogenic cell death and reversing immunosuppression
Author
Lu, Jianqin 1   VIAFID ORCID Logo  ; Liu, Xiangsheng 2 ; Yu-Pei, Liao 3 ; Salazar, Felix 4 ; Sun, Bingbing 3   VIAFID ORCID Logo  ; Jiang, Wen 5   VIAFID ORCID Logo  ; Chang, Chong Hyun 6 ; Jiang, Jinhong 5 ; Wang, Xiang 5 ; Wu, Anna M 4 ; Meng, Huan 7 ; Nel, Andre E 7 

1  Division of NanoMedicine, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Center for Environmental Implications of Nanotechnology, California NanoSystems Institute, University of California, Los Angeles, CA, USA; California NanoSystems Institute, University of California, Los Angeles, CA, USA 
2  Division of NanoMedicine, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; California NanoSystems Institute, University of California, Los Angeles, CA, USA 
3  Division of NanoMedicine, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA 
4  Department of Molecular and Medical Pharmacology Crump Institute for Molecular Imaging, David Geffen School of Medicine, Los Angeles, CA, USA 
5  Center for Environmental Implications of Nanotechnology, California NanoSystems Institute, University of California, Los Angeles, CA, USA 
6  Center for Environmental Implications of Nanotechnology, California NanoSystems Institute, University of California, Los Angeles, CA, USA; California NanoSystems Institute, University of California, Los Angeles, CA, USA 
7  Division of NanoMedicine, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Center for Environmental Implications of Nanotechnology, California NanoSystems Institute, University of California, Los Angeles, CA, USA; California NanoSystems Institute, University of California, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA 
Pages
1-14
Publication year
2017
Publication date
Nov 2017
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-017-01651-9
ProQuest document ID
1968993856
Copyright
© 2017. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.