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.
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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.
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