Effects of the pharmacological activation of Liver X Receptors in the tumor microenvironment

dc.contributor
Universitat de Barcelona. Departament de Biologia Cel·lular, Fisiologia i Immunologia
dc.contributor.author
Font Díaz, Joan
dc.date.accessioned
2022-11-17T08:24:08Z
dc.date.available
2023-07-22T22:45:22Z
dc.date.issued
2022-07-22
dc.identifier.uri
http://hdl.handle.net/10803/676013
dc.description
Programa de Doctorat en Biomedicina
dc.description.abstract
Nuclear receptors are a superfamily of ligand-dependent transcription factors that are involved in numerous biological processes in homeostasis and disease. Liver X receptors (LXRs) are members of the nuclear receptors family that are regulated by oxidized forms of cholesterol (oxysterols) and other byproducts of cholesterol metabolism and biosynthesis. In addition, there are synthetic agonists, such as T0901317 (T1317), which have higher affinity and stability. LXRs are key factors in the regulation of lipid homeostasis and in the modulation of inflammation. There are two LXRs isoforms, LXRα (NR1H3) and LXRβ (NR1H2), encoded by two different genes and with differential tissue distribution. In order to bind to the DNA and regulate the expression of target genes, LXRs form heterodimers with the retinoid X receptors (RXRs), another member of the nuclear receptors family. LXRs can also repress the expression of genes, for example interacting with co-repressor complexes through transrepression. In the last decade, there has been a growing interest in LXRs as therapeutic targets against cancer. Activation of LXRs with high doses of synthetic agonists exerts direct antiproliferative, cytostatic and pro-apoptotic effects in vitro in many cancer cell lines. In addition, pharmacological activation of LXRs can inhibit tumor progression in pre- clinical models in mice. Interestingly, in our own previous studies using a syngeneic model of Lewis lung carcinoma, activation of the LXR pathway with T1317 suppressed tumor growth in wild type but not in LXR-deficient mice, underlining the importance of functional expression of LXRs in the host for the antitumoral effects of the agonist. In addition, the expression of the chemokines CCL17 and CCL22, key attractants for regulatory T (Treg) cells, and the transcription factor IRF4 was inhibited in T1317-treated TAMs in vivo and ex vivo. Based on these observations, we further explored the actions of the LXR agonist in the tumor microenvironment. Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment, and they strongly contribute to the establishment of an immunosuppressive environment. We studied two TAM subpopulations with distinct phenotypic characteristics and intra-tumoral localization, named MHCIIhigh TAMs and MHCIIlow TAMs after their differential expression of MHCII. Collectively, treatment with T1317 impacted the transcriptional profile of TAMs at multiple levels, suppressing several mechanisms used by these cells for the maintenance of the immunosuppressed environment. Among these effects, activation of LXRs caused a decrease in the abundance of Tregs in the tumor, without affecting their immunosuppressive or proliferative capabilities, nor their peripheral abundance. Concomitantly with the inhibition of CCL17 expression in TAMs, the results suggested that LXR activation reduced Treg intratumoral abundance through blocking their recruitment. In this sense, a functional systemic expression of IRF4 was found necessary for the T1317-mediated inhibition of tumor growth. In addition, the inhibitory effect of LXR activation on CCL17, CCL22 and IRF4 expression was also observed in human macrophages derived from peripheral mononuclear cells from healthy donors, suggesting that the crosstalk between LXRs and the IRF4- CCL17/CCL22 axis is evolutionary conserved and may be also relevant in humans. Overall, these results shed new light on the mechanisms of LXR agonists as antitumoral drugs targeting the tumor microenvironment.
dc.format.extent
195 p.
dc.format.mimetype
application/pdf
dc.language.iso
eng
dc.publisher
Universitat de Barcelona
dc.rights.license
ADVERTIMENT. Tots els drets reservats. L'accés als continguts d'aquesta tesi doctoral i la seva utilització ha de respectar els drets de la persona autora. Pot ser utilitzada per a consulta o estudi personal, així com en activitats o materials d'investigació i docència en els termes establerts a l'art. 32 del Text Refós de la Llei de Propietat Intel·lectual (RDL 1/1996). Per altres utilitzacions es requereix l'autorització prèvia i expressa de la persona autora. En qualsevol cas, en la utilització dels seus continguts caldrà indicar de forma clara el nom i cognoms de la persona autora i el títol de la tesi doctoral. No s'autoritza la seva reproducció o altres formes d'explotació efectuades amb finalitats de lucre ni la seva comunicació pública des d'un lloc aliè al servei TDX. Tampoc s'autoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant als continguts de la tesi com als seus resums i índexs.
dc.source
TDX (Tesis Doctorals en Xarxa)
dc.subject
Oncologia
dc.subject
Oncología
dc.subject
Oncology
dc.subject
Macròfags
dc.subject
Macrófagos
dc.subject
Macrophages
dc.subject
Receptors nuclears (Bioquímica)
dc.subject
Receptores nucleares (Bioquímica)
dc.subject
Nuclear receptors (Biochemistry)
dc.subject
Cèl·lules T
dc.subject
Células T
dc.subject
T cells
dc.subject
Tumors
dc.subject
Tumores
dc.subject.other
Ciències Experimentals i Matemàtiques
dc.title
Effects of the pharmacological activation of Liver X Receptors in the tumor microenvironment
dc.type
info:eu-repo/semantics/doctoralThesis
dc.type
info:eu-repo/semantics/publishedVersion
dc.subject.udc
616
dc.contributor.director
Valledor Fernández, Annabel
dc.contributor.tutor
Valledor Fernández, Annabel
dc.rights.accessLevel
info:eu-repo/semantics/openAccess


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