Tumor-mediated liver X receptor-α activation inhibits CC chemokine receptor-7 expression on dendritic cells and dampens antitumor responses

Villablanca, E. J. et al. Nat. Med. 16:98-105 (2010)

Speaker: Bernard Kiro (祁晨恩)                                           Time: 13:00~14:00, Apr 28, 2010

Commentator: Yao Chang, Ph.D. (張　堯博士)          Place: Room 601

Abstract:

Recently, some strategies of tumor evading immune response have been elucidated. Among them is the activation of various metabolic pathways leading to immunosuppressive effect. How the metabolic product of cholesterol effects the immune response is still unclear. Liver X receptors (LXRs, LXRa and LXRb), members of the nuclear receptor superfamily, are lipid-activated transcription factors located in the nucleus, which are key regulators of lipid metabolism, inflammation and proliferation^1,2. Oxysterols, natural ligand for LXRs, are the product of cholesterol oxygenation in the steps of degradation of cholesterol to bile acid and its conversion to steroid hormones³. MSR3 (human melanoma cell line) condition medium and MSR3-CD40L (melanoma cell expressing CD40 ligand) can inhibit the expression of CCR7 receptor on human and mouse dendritic cells (DCs), but the inhibitory activity does not interfere with the expression of antigen-presenting and co-stimulatory molecules, cytokine release and allogeneic T cell stimulatory ability. Inhibition of CCR7 was functional, as DCs exposed to MSR3 condition medium or MSR3-CD40L migrated less efficiently to the CCR7 ligand CCL19. Previous studies have demonstrated that agonist of some nuclear receptors inhibits the expression of CCR7 and CXCR4 on human and mouse DCs. By luciferase reporter assay, MSR3 condition medium have shown to activate LXRa, in contrast to non-inhibitory tumor. Furthermore, blocking cholesterol and oxysterol synthesis by zaragozic acid or inactivation of natural oxysterols by sulfotransferase SULT2B1b abrogates CCR7 inhibition. These findings highlight a new strategy for tumor immunoescape.

References:

1.      Bensinger, S.J. et al. LXR signaling couples sterol metabolism to proliferation in the acquired immune response. Cell 134, 97–111 (2008).

2.      Bensinger, S.J. & Tontonoz, P. Integration of metabolism and inflammation by lipid-activated nuclear receptors. Nature 454, 470–477 (2008).

3.      Björkhem, I. Do oxysterols control cholesterol homeostasis? J. Clin. Invest. 110, 725–730 (2002).