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

Nat Commun. 2017 Nov 27;8(1):1811. doi: 10.1038/s41467-017-01651-9.

Authors

Jianqin Lu^{1

2

3}, Xiangsheng Liu^{1

3}, Yu-Pei Liao¹, Felix Salazar⁴, Bingbing Sun¹, Wen Jiang², Chong Hyun Chang^{2

3}, Jinhong Jiang², Xiang Wang², Anna M Wu⁴, Huan Meng^{5

6

7

8}, Andre E Nel^{9

10

11

12}

Affiliations

¹ Division of NanoMedicine, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.
² Center for Environmental Implications of Nanotechnology, California NanoSystems Institute, University of California, Los Angeles, CA, 90095, USA.
³ California NanoSystems Institute, University of California, Los Angeles, CA, 90095, USA.
⁴ Department of Molecular and Medical Pharmacology Crump Institute for Molecular Imaging, David Geffen School of Medicine, Los Angeles, CA, 90095, USA.
⁵ Division of NanoMedicine, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA. hmeng@mednet.ucla.edu.
⁶ Center for Environmental Implications of Nanotechnology, California NanoSystems Institute, University of California, Los Angeles, CA, 90095, USA. hmeng@mednet.ucla.edu.
⁷ California NanoSystems Institute, University of California, Los Angeles, CA, 90095, USA. hmeng@mednet.ucla.edu.
⁸ Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, 90095, USA. hmeng@mednet.ucla.edu.
⁹ Division of NanoMedicine, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA. anel@mednet.ucla.edu.
¹⁰ Center for Environmental Implications of Nanotechnology, California NanoSystems Institute, University of California, Los Angeles, CA, 90095, USA. anel@mednet.ucla.edu.
¹¹ California NanoSystems Institute, University of California, Los Angeles, CA, 90095, USA. anel@mednet.ucla.edu.
¹² Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, 90095, USA. anel@mednet.ucla.edu.

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Adaptive Immunity / drug effects
Animals
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
Apoptosis / immunology
Carcinoma, Pancreatic Ductal / immunology
Carcinoma, Pancreatic Ductal / therapy*
Cell Line, Tumor
Drug Carriers / chemistry
Feasibility Studies
Female
Forkhead Transcription Factors / metabolism
Humans
Immune Tolerance / drug effects*
Immunity, Innate / drug effects
Immunotherapy / methods*
Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors
Indoleamine-Pyrrole 2,3,-Dioxygenase / immunology
Male
Mice
Nanoparticles / chemistry
Organoplatinum Compounds / pharmacology
Oxaliplatin
Pancreatic Neoplasms / immunology
Pancreatic Neoplasms / therapy*
Phospholipids / chemistry
Porosity
Prodrugs / metabolism
Prodrugs / pharmacology
Silicon Dioxide / chemistry
T-Lymphocytes, Cytotoxic / drug effects
T-Lymphocytes, Cytotoxic / immunology
T-Lymphocytes, Cytotoxic / metabolism
Tissue Distribution
Tryptophan / analogs & derivatives*
Tryptophan / metabolism
Tryptophan / pharmacology
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Drug Carriers
Forkhead Transcription Factors
Foxp3 protein, mouse
IDO1 protein, mouse
Indoleamine-Pyrrole 2,3,-Dioxygenase
Organoplatinum Compounds
Phospholipids
Prodrugs
Oxaliplatin
Silicon Dioxide
Tryptophan
1-methyltryptophan

Abstract

Publication types

MeSH terms

Substances

Grants and funding