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Title: Pharmacological activation of LXR alters the expression profile of tumor-associated macrophages and the abundance of regulatory T cells in the tumor microenvironment
Author: Carbó, José M.
León Moreno, Theresa Elizabeth
Font-Díaz, Joan
De la Rosa, Juan Vladimir
Castrillo, Antonio
Picard, Felix R.
Staudenraus, Danel
Huber, Magdalena
Cedó Giné, Lídia
Escolà-Gil, Joan Carles
Campos, Lucía
Bakiri, Latifa
Wagner, Erwin F.
Caelles Franch, Carme
Stratmann, Thomas
Van Ginderachter, J.A.
Valledor Fernández, Annabel
Keywords: Receptors nuclears (Bioquímica)
Nuclear receptors (Biochemistry)
Issue Date: 23-Dec-2020
Publisher: American Association for Cancer Research
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 anti-tumor 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 anti-tumor effects of the agonist depends on functional LXR activity in host cells. Pharmacological 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 IL-4, 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 anti-tumoral effects of pharmacological LXR activation. Moreover, these data provide new insights for the development of novel therapeutic options for the treatment of cancer.
Note: Versió postprint del document publicat a:
It is part of: Cancer Research, 2020, vol. 81, num. 4
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ISSN: 0008-5472
Appears in Collections:Articles publicats en revistes (Bioquímica i Fisiologia)
Articles publicats en revistes (Biologia Cel·lular, Fisiologia i Immunologia)

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