Pharmacologic Activation of LXR Alters the Expression Profile of Tumor-Associated Macrophages and the Abundance of Regulatory T Cells in the Tumor Microenvironment
Open Access
- 15 February 2021
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 81 (4), 968-985
- https://doi.org/10.1158/0008-5472.CAN-19-3360
Abstract
Liver X receptors (LXR) are transcription factors from the nuclear receptor family that are activated by oxysterols and synthetic high-affinity agonists. In this study, we assessed the antitumor effects of synthetic LXR agonist TO901317 in a murine model of syngeneic Lewis Lung carcinoma. Treatment with TO901317 inhibited tumor growth in wild-type, but not in LXR-deficient mice, indicating that the antitumor effects of the agonist depends on functional LXR activity in host cells. Pharmacologic activation of the LXR pathway reduced the intratumoral abundance of regulatory T cells (Treg) and the expression of the Treg-attracting chemokine Ccl17 by MHCIIhigh tumor-associated macrophages (TAM). Moreover, gene expression profiling indicated a broad negative impact of the LXR agonist on other mechanisms used by TAM for the maintenance of an immunosuppressive environment. In studies exploring the macrophage response to GM-CSF or IL4, activated LXR repressed IRF4 expression, resulting in subsequent downregulation of IRF4-dependent genes including Ccl17. Taken together, this work reveals the combined actions of the LXR pathway in the control of TAM responses that contribute to the antitumoral effects of pharmacologic LXR activation. Moreover, these data provide new insights for the development of novel therapeutic options for the treatment of cancer. Significance: This study reveals unrecognized roles of LXR in the transcriptional control of the tumor microenvironment and suggests use of a synthetic LXR agonist as a novel therapeutic strategy to stimulate antitumor activity.Funding Information
- MINECO (SAF2017-89510-R, SAF2014-57856-P)
- MINECO (SAF2014-56819-R)
- MINECO (SAF2017-90604-REDT, SAF2015-71878-REDT)
- MICINN (SAF2011-23402, SAF2010-14989)
- Fundació la Marató de TV3 (080930)
- DFG (1824/5-1, 1824/7-1, 1824/9-1)
- Instituto de Salud Carlos III (FIS 16/00139)
- FPI (PRE2018-085579)
This publication has 57 references indexed in Scilit:
- A Validated Regulatory Network for Th17 Cell SpecificationCell, 2012
- Accumulation of Myeloid-Derived Suppressor Cells in the Lungs during Pneumocystis PneumoniaInfection and Immunity, 2012
- BATF–JUN is critical for IRF4-mediated transcription in T cellsNature, 2012
- Activation of liver X receptor increases acetaminophen clearance and prevents its toxicity in miceHepatology, 2011
- LXR promotes the maximal egress of monocyte-derived cells from mouse aortic plaques during atherosclerosis regressionJCI Insight, 2010
- Different Tumor Microenvironments Contain Functionally Distinct Subsets of Macrophages Derived from Ly6C(high) MonocytesCancer Research, 2010
- Anti-proliferative effect of LXR agonist T0901317 in ovarian carcinoma cellsJournal of Ovarian Research, 2010
- Apoptotic Cells Promote Their Own Clearance and Immune Tolerance through Activation of the Nuclear Receptor LXRImmunity, 2009
- LXR Signaling Couples Sterol Metabolism to Proliferation in the Acquired Immune ResponseCell, 2008
- Oncogenic pathway signatures in human cancers as a guide to targeted therapiesNature, 2005