Work

Inhibition of FXR singnaling in tumor-associated myeloid cells protects against melanoma progression 2094

Year: 2025

Type: article

Abstract: Description Our study delves into the complex interplay between the tumor microenvironment and immune cell regulation, with a particular focus on myeloid-derived suppressor cells (MDSCs). A key discovery of our research is the accumulation of bile acids (BAs) within the tumor microenvironment and tumor-infiltrating myeloid cells. BAs significantly enhance the suppressive function of MDSCs via activation of Farnesoid X Receptor (FXR). Using melanoma as our primary model. We demonstrate that modulation of MDSCs’ suppressive function can be achieved through the targeting FXR using specific agents like GW4064 and z-Guggulsterone (z-GS). Myeloid-specific elimination of FXR via Lysozyme M Cre led to a significant delay in tumor progression. This was accompanied by the reduction of PMN-MDSC and an increased infiltration of CD45+ immune cells and a surge in the presence of anti-tumor specific T cells. Administration of FXR inhibitor, z-GS, also reduced tumor size in vivo. Additionally, targeting FXR by z-GS or genetic ablation enhances adoptive T cells transfer therapy efficacy. MDSCs with impaired FXR signaling result in reduced mitochondria activity and downregulation of Arg1. Furthermore, an enhanced antigen presentation function is observed in MDSCs treated with z-GS. Our research presents a compelling case for targeting FXR signaling in myeloid cells as a novel therapeutic strategy and open new pathways for enhancing anti-tumoral immunity. Funding Sources Supported by NIH/R01CA262121-01 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Source: The Journal of Immunology

DOI: 10.1093/jimmun/vkaf283.058