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Published on: February 2, 2024
Detection and Functional Analysis of Tumor-Derived LXR Ligands
Raffaella Fontana1, Aida Paniccia1, Vincenzo Russo2
1Cancer Gene Therapy Unit, IRCCS San Raffaele Hospital, Via Olgettina 58, Milano, 21032, Italy.
Abstract:
There is growing evidence highlighting the ability of nuclear receptors to control not only metabolism, but also inflammation and cancer progression. In particular liver X receptors (LXRs), the nuclear receptors physiologically involved in cholesterol homeostasis, have been shown to regulate innate and adaptive immune responses in many pathological conditions, including cancer.We have recently demonstrated that LXR ligands (oxysterols) released by tumor cells may have an immunomodulatory role, affecting the immune cells involved in the antitumor immune response. Indeed, oxysterols inhibit the expression of the chemokine receptor CCR7 on dendritic cells (DC) in an LXR-dependent manner, thus impairing DC migration to secondary lymphoid organs, and therefore dampening the induction of successful antitumor responses.We have resorted to direct (i.e., luciferase-based LXR activation assay) and indirect (i.e., activation of LXR target genes in dendritic cells) methods in order to assess the presence of LXR ligands (oxysterols) in tumor-conditioned media.These two methods are also suitable to study strategies to block oxysterol release by tumor cells.
Insights
Tumor-released oxysterols, acting as liver X receptor (LXR) ligands, hinder dendritic cell migration, thus suppressing anti-tumor immunity. This study identifies a novel mechanism impacting cancer immune responses.
Area of Science:
- Immunology
- Molecular Biology
- Oncology
Background:
- Nuclear receptors, including liver X receptors (LXRs), play crucial roles in metabolism, inflammation, and cancer progression.
- LXRs are key regulators of cholesterol homeostasis and influence immune responses in various pathologies, notably cancer.
Purpose of the Study:
- To investigate the immunomodulatory role of LXR ligands (oxysterols) released by tumor cells.
- To understand how tumor-derived oxysterols affect anti-tumor immune responses by targeting immune cells like dendritic cells (DCs).
Main Methods:
- Utilized direct (luciferase-based LXR activation assay) and indirect (LXR target gene activation in DCs) methods.
- Assessed the presence of oxysterols in tumor-conditioned media to evaluate LXR ligand activity.
Main Results:
- Demonstrated that tumor-released oxysterols inhibit LXR-dependent expression of the chemokine receptor CCR7 on dendritic cells.
- Showed that this inhibition impairs DC migration to lymphoid organs, consequently dampening anti-tumor immune responses.
Conclusions:
- Tumor-derived oxysterols act as LXR ligands that suppress anti-tumor immunity by impairing DC function.
- The developed methods are suitable for studying strategies to block oxysterol release and potentially enhance anti-tumor responses.
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