Dataset Information

Farnesyl diphosphate synthase inhibition remodels the tumor immune microenvironment by activating endogenous retroviruses

ABSTRACT: Farnesyl diphosphate synthase (FDPS) is a crucial enzyme in isoprenoid and cholesterol biosynthesis and the target for nitrogen-containing bisphosphonate (N-BP) drugs widely used for osteoporosis treatment. Here we show that FDPS inhibition overcomes tumor resistance to immune checkpoint blockade (ICB) therapy by activating endogenous retroviruses (ERVs) and promoting a potent type I interferon response. FDPS inhibition, either by genetic knockout or alendronate, enhances the efficacy of ICB therapy substantially in multiple murine tumors by remodeling the immune microenvironment and enhancing lymphocyte infiltration, which is caused by increased type I interferon upregulation. Mechanistically, FDPS inhibition attenuates mitochondrial membrane potential (MtMP), enabling endonuclease G (EndoG) migration from the mitochondria into the nucleus, increasing DNA double-strand breaks and degradation of the heterochromatin maintenance protein TRIM28(KAP1), promoting enhanced ERV transcription and activation of the MDA5/MAVS pathway. The ensuing type I interferon upregulation is responsible for enhanced antigen presentation and sensitization to ICB therapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE281577 | GEO | 2024/11/14

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Liver fibrosis is a hard-to-treat disease with liver transplantation as only effective curation to this date. During disease progression, immune suppressive macrophages dominate and support fibrosis formation by replacement of functional parenchyma with collagen-dominating scare tissue. To alter the macrophage behavior, a pH-degradable, nanogel-based delivery system was developed for the covalent conjugation of the clinically approved bisphosphonate alendronate. The nanocarrier mediates the drugs’ delivery into hepatic nonparenchymal cells after intravenous administration and, thereby, triggers a macrophage repolarization against fibrosis progression. This approach may provide a significant contribution to establish further nanotherapeutic delivery strategies to effectively treat liver fibrosis. Immune suppressive macrophages contribute to the progression of several diseases including cancer and fibrosis. Especially in chronically damaged liver tissues they trigger the replacement of functional parenchyma by collagen-dominating scare tissue. In this study, we aimed to intervene into this cascade by repolarizing the macrophage phenotype via a pH-degradable, squaric ester-based nanogel carrier system. This nanotechnology platform enables a selective covalent conjugation of the highly water-soluble bisphosphonate alendronate and, thus, its safe and efficient delivery to hepatic nonparenchymal cells of fibrotic livers after intravenous administration. The bisphosphonate triggers a reprogramming of profibrotic M2- towards antifibrotic M1-phenotype macrophages affording an fibrolytic outcome, as verified both on mRNA and protein level. Further insights by genomic and proteomic studies confirm the macrophages’ repolarization and thus corroborate the virtue of the nanogels as biocompatible nanocarrier platform for hepatotropic bisphosphonate delivery. Beyond preventing liver fibrosis progression, these nanogels may therefore represent an attractive device for further nanotherapeutic interventions in M2-type macrophage dominating diseases.

Dataset Information

Farnesyl diphosphate synthase inhibition remodels the tumor immune microenvironment by activating endogenous retroviruses

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets