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Pharmacological activation of LXR alters the expression profile of tumor-associated macrophages and the abundance of regulatory T cells in the tumor microenvironment
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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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CARBÓ, José m., LEÓN MORENO, Theresa elizabeth, FONT DÍAZ, Joan, ROSA, Juan vladimir de la, 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. Pharmacological activation of LXR alters the expression profile of tumor-associated macrophages and the abundance of regulatory T cells in the tumor microenvironment. _Cancer Research_. 2020. Vol. 81, núm. 4. [consulta: 21 de gener de 2026]. ISSN: 0008-5472. [Disponible a: https://hdl.handle.net/2445/175887]