Breast Cancer Chemo-immunotherapy through Liposomal Delivery of an Immunogenic Cell Death Stimulus Plus Interference in the IDO-1 Pathway

Jianqin Lu, Xiangsheng Liu, Yu Pei Liao, Xiang Wang, Ayman Ahmed, Wen Jiang, Ying Ji, Huan Meng, Andre E. Nel

Research output: Contribution to journalArticlepeer-review

156 Scopus citations

Abstract

Immunotherapy provides the best approach to reduce the high mortality of metastatic breast cancer (BC). We demonstrate a chemo-immunotherapy approach, which utilizes a liposomal carrier to simultaneously trigger immunogenic cell death (ICD) as well as interfere in the regionally overexpressed immunosuppressive effect of indoleamine 2,3-dioxygenase (IDO-1) at the BC tumor site. The liposome was constructed by self-assembly of a phospholipid-conjugated prodrug, indoximod (IND), which inhibits the IDO-1 pathway, followed by the remote loading of the ICD-inducing chemo drug, doxorubicin (DOX). Intravenous injection of the encapsulated two-drug combination dramatically improved the pharmacokinetics and tumor drug concentrations of DOX and IND in an orthotopic 4T1 tumor model in syngeneic mice. Delivery of a threshold ICD stimulus resulted in the uptake of dying BC cells by dendritic cells, tumor antigen presentation and the activation/recruitment of nalve T-cells. The subsequent activation of perforin- and IFN-Î releasing cytotoxic T-cells induced robust tumor cell killing at the primary as well as metastatic tumor sites. Immune phenotyping of the tumor tissues confirmed the recruitment of CD8+ cytotoxic T lymphocytes (CTLs), disappearance of Tregs, and an increase in CD8+/FOXP3+ T-cell ratios. Not only does the DOX/IND-Liposome provide a synergistic antitumor response that is superior to a DOX-only liposome, but it also demonstrated that the carrier could be effectively combined with PD-1 blocking antibodies to eradicate lung metastases. All considered, an innovative nano-enabled approach has been established to allow deliberate use of ICD to switch an immune deplete to an immune replete BC microenvironment, allowing further boosting of the response by coadministered IDO inhibitors or immune checkpoint blocking antibodies.

Original languageEnglish (US)
Pages (from-to)11041-11061
Number of pages21
JournalACS Nano
Volume12
Issue number11
DOIs
StatePublished - Nov 27 2018
Externally publishedYes

Keywords

  • breast cancer
  • chemo-immunotherapy
  • doxorubicin
  • dual-delivery liposome
  • immune checkpoint
  • immunogenic cell death
  • indoleamine 2,3-dioxygenase

ASJC Scopus subject areas

  • Materials Science(all)
  • Engineering(all)
  • Physics and Astronomy(all)

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