Nano-enabled pancreas cancer immunotherapy using immunogenic cell death and reversing immunosuppression.
Jianqin LuXiangsheng LiuYu-Pei LiaoFelix SalazarBingbing SunWen JiangChong Hyun ChangJinhong JiangXiang WangAnna M WuHuan MengAndre E NelPublished in: Nature communications (2017)
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.
Keyphrases
- cell death
- immune response
- cancer therapy
- cell cycle arrest
- drug delivery
- drug release
- fatty acid
- low density lipoprotein
- regulatory t cells
- social media
- dendritic cells
- toll like receptor
- locally advanced
- ultrasound guided
- metabolic syndrome
- helicobacter pylori
- inflammatory response
- high fat diet induced
- current status
- pi k akt
- walled carbon nanotubes