Dataset Information

Imiquimod-Loaded Phospholipid-Free Unilamellar Vesicles Activate the Tumor Immune Microenvironment to Treat Liver Cancer and Liver Metastases

ABSTRACT: Liver cancers are often diagnosed at advanced stages and the fourth most common cause of cancer death globally. Addition to primary tumours, liver metastases are also common from other cancer sites like colorectal cancers, where 66% of patients develop this condition. Immunotherapies for these diseases have been hindered by the immunosuppressive microenvironment. Our lab has developed phospholipid-free unilamellar vesicles (PFSUV) to localize a toll-like receptor 7 agonist Imiquimod (IMQ), to the hepatocytes. PFSUV is composed of 83 mol% cholesterol and 17 mol% Tween80 and IMQ was loaded inside the aqueous core of these 75-nm particles. When administered intravenously (i.v.), PFSUV-IMQ was found to sustain IFN-α levels in the liver over 24 hours, with significantly lower plasma IFN-α levels compared to free IMQ. In a mouse model of liver metastasis from a colorectal cancer origin generated with CT26 cells, mice treated with PFSUV-IMQ in combination with Oxaliplatin showed a significant reduction in tumour size, with increases in CD8+ T cell and a higher percentage of apoptotic cells in the tumour compared to controls. In a mouse model of primary liver cancer using HCA-1 cells, the same treatment combination also showed a significant decrease in tumour burden, increased apoptotic cell percentage in the tumour, and significantly reduced lung metastasis from the liver compared to controls. Flow cytometry analysis showed tumours treated with PFSUV-IMQ had increased infiltration of CD86+/MHC-II+ dendritic cells and IFN-y+ CD8+ T cells. RNA-seq showed an enrichment of innate immune activation genes after a single dose of PFSUV-IMQ. Overall, these data suggest that the activation of the tumour immune microenvironment through this targeted delivery of IMQ resulted in a decrease in tumour burden across both liver tumour models.

ORGANISM(S): Mus musculus

PROVIDER: GSE289163 | GEO | 2025/03/01

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Purpose: miR-181 is upregulated in human liver cancer. The cancer genome atlas (TCGA) liver cancer data show that the iCluster1 subclass of hepatocellular carcinoma (HCC) has a higher expression of miR-181 than either the iCluster2 or iCluster3 subclass, suggesting it may be a driver of oncogenesis. However, the miR-181 family has also been reported to inhibit tumour progression. Thus, we aim to examine the function of miR-181 and its vital mediators in hepatocarcinogenesis. Methods: Primary liver tumours were induced with diethylnitrosamine (DEN) in global (miR-181ab1GKO), liver-specific (miR-181ab1LKO) and hematopoietic & endothelial lineage-specific (miR-181ab1vavKO) miR-181ab1 deletion mice. The molecular and cellular characterization was carried out using immunohistochemistry and whole-genome transcriptome analysis. Liver-specific miR-181a and CBX7 double knockout mice were used to investigate the role of CBX7 in mediating miR-181 effects on liver tumour progression. An AAV/Transposase Hybrid-Vector System used in this study gave a reliable long-term expression of CBX7 in vivo. Relevant gene expression profiles and patient outcomes were downloaded from TCGA database, and their correlations were analysed. The mRNA profiles of miR-181ab1 wild-type (WT) and knockout (KO) mice were generated by deep sequencing, in triplicate, using Illumina HiSeq. After quality control procedures, short reads were mapped to mouse genome assembly (mm10) by STAR version 2.7.3a. Mapped reads were quantified by featureCounts version 2.0.0 from Subread package. Ward’s hierarchical clustering method was applied to group the samples based on the gene expression matrix. Differential gene expression analysis was then conducted using R package Limma. Gene set enrichment analysis was subsequently performed with R package clusterProfiler. Overlaps between differential expressed gene sets and gene sets in MSigDB were computed with Gene Set Enrichment Analysis (GSEA). Results: The number and size of liver tumours in 181ab1GKO mice were significantly reduced by 50% and 90%, respectively, compared to WT mice at 34-week post-DEN injection. The number of tumours in 181ab1LKO mice was no different from that of control mice, but the size of liver tumours was significantly reduced by 90%. The number and size of tumours were similar in miR-181ab1vavKO and WT mice. Consistent with the roles of miR-181 in the promotion of epithelial to mesenchymal transition (EMT), the TGF-beta signalling pathway was inhibited in 181ab1GKO tumours compared with WT tumours, and expression of E-Cadherin, an EMT marker, was significantly increased in miR-181ab1 KO tumours compared to WT tumours. CBX7 was reduced in WT liver tumours compared to non-tumours, and restored CBX7 expression inhibited the progression of liver tumours in WT mice. At the same time, CBX7 was upregulated in miR-181ab1 KO tumours compared to WT tumours, and CBX7 deletion turned the reduced progression of miR-181ab1 KO liver tumours back to WT liver tumours. MiR-181a expression was the lowest and CBX7 expression the highest in iCluster 2 & 3 subclasses of human HCC compared to iCluster 1. Gene expression profiles were significantly overlapped between human low proliferative periportal-type HCCs and miR-181ab1 KO tumours. Conclusions: Primary liver tumour progression is inhibited by loss of miR-181ab1 via up-regulation of CBX7 expression at the level of the liver cancer cells themselves, but tumour induction requires both hepatic and non-hepatic expression. Tumours in miR-181ab1 KO mice resemble low-proliferative periportal-type human HCC and could represent a new model to study therapies for such difficult-to-treat tumours.

Dataset Information

Imiquimod-Loaded Phospholipid-Free Unilamellar Vesicles Activate the Tumor Immune Microenvironment to Treat Liver Cancer and Liver Metastases

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets