Nuclear receptor ligands induce TREM-1 expression on dendritic cells: analysis of their role in tumors

ABSTRACT

Dendritic cells (DCs) initiate adaptive immune responses after their migration to secondary lymphoid organs. The LXR ligands/oxysterols and the RXR ligand 9-cis Retinoic Acid (9-cis RA) were shown to dampen DC migration to lymphoid organs through the inhibition of CCR7 expression. We performed transcriptomics of DCs undergoing maturation in the presence of the LXR ligand 22R-Hydroxycholesterol (22R-HC). The analysis highlighted more than 1500 genes modulated by 22R-HC treatment, including the triggering receptor expressed on myeloid cells (TREM)-1, which was found markedly up-regulated. We tested the effect of other nuclear receptor ligands (NRL) and we reported the induction of TREM-1 following RXR, RAR and VDR activation. From a functional point of view, triggering of TREM-1 induced by retinoids increased TNFα and IL-1β release, suggesting an active role of NRL-activated TREM-1⁺ DCs in inflammation-driven diseases, including cancer. Consistently with this hypothesis we detected DCs expressing TREM-1 in pleural effusions and ascites of cancer patients, an observation validated by the induction of TREM-1, LXR and RAR target genes when monocyte-DCs were activated in the presence of tumor-conditioned fluids. Finally, we observed a better control of LLC tumor growth in Trem-1^−/- bone marrow chimera mice as compared to wild type chimera mice. Future studies will be necessary to shed light on the mechanism of TREM-1 induction by distinct NRL, and to characterize the role of TREM-1⁺ DCs in tumor growth.

KEYWORDS:

• LXR nuclear receptors
• RAR/RXR nuclear receptors
• dendritic cells
• TREM-1
• lung cancer
• ovarian cancer

Acknowledgments

We thank Elisa Lenti and Noemi Di Meglio for technical help. We are grateful to Catia Traversari for discussion and suggestions. This work was funded by the Italian Association for Cancer Research (AIRC) (IG 19016) and the Italian Ministry of Health (RF2009). L.Ra. is recipient of a fellowship from the “Fondazione Umberto Veronesi”.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Author Contributions

R.F., L.R., K.R.S., C.B. M.C. and V.R. designed research; R.F., L.R., L.Ra., A.P., T.J., D.M., C.D., M.M., and C.B. performed research; G.M., A.B., G.Ma. and A.B. provided clinical samples and patients’ clinical data. M.Ce. and M.C. provided TREM-1 reagents and Trem-1,3^−/- mice. K.R.S. provided reagents for LXR ChIP experiments. R.C. performed correlative studies among TREM-1, ABCA1 and TGM-2 gene expression. R.F., L.Ra., C.B. and V.R. analyzed data; R.F. and V.R. wrote the paper.

Supplementary material

Supplemental data for this article can be accessed in publishers website.

Additional information

Funding

This work was supported by the Associazione Italiana per la Ricerca sul Cancro [IG 19016];Fondazione Umberto Veronesi [NA];Ministero della Salute [RF2009];