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Pharmacologic Activation of LXR Alters the Expression Profile of Tumor-Associated Macrophages and the Abundance of Regulatory T Cells in the Tumor Microenvironment

Carbó, JM; León, TE; Font-Díaz, J; De la Rosa, JV; Castrillo, A; Picard, FR; Staudenraus, D; ... Valledor, AF; + view all (2021) Pharmacologic Activation of LXR Alters the Expression Profile of Tumor-Associated Macrophages and the Abundance of Regulatory T Cells in the Tumor Microenvironment. Cancer Research , 81 (4) pp. 968-985. 10.1158/0008-5472.CAN-19-3360. Green open access

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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.

Type: Article
Title: Pharmacologic Activation of LXR Alters the Expression Profile of Tumor-Associated Macrophages and the Abundance of Regulatory T Cells in the Tumor Microenvironment
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1158/0008-5472.CAN-19-3360
Publisher version: https://doi.org/10.1158/0008-5472.CAN-19-3360
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
URI: https://discovery.ucl.ac.uk/id/eprint/10120386
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