Pharmacologic Activation of LXR Alters the Expression Profile of Tumor-Associated Macrophages and the Abundance of Regulatory T Cells in the Tumor Microenvironment
Por:
Carbo, JM, Leon, TE, Font-Diaz, J, De la Rosa, JV, Castrillo, A, Picard, FR, Staudenraus, D, Huber, M, Cedo, L, Escola-Gil, JC, Campos, L, Bakiri, L, Wagner, EF, Caelles, C, Stratmann, T, Van Ginderachter, JA, Valledor, AF
Publicada:
15 feb 2021
Resumen:
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 antitumor 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 antitumor effects of the agonist depends on functional LXR activity in host cells. Pharmacologic 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 IL4, 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 antitumoral effects of pharmacologic LXR activation. Moreover, these data provide new insights for the development of novel therapeutic options for the treatment of cancer.
Significance: This study reveals unrecognized roles of LXR in the transcriptional control of the tumor microenvironment and suggests use of a synthetic LXR agonist as a novel therapeutic strategy to stimulate antitumor activity.
Filiaciones:
Carbo, JM:
Univ Barcelona, Sch Biol, Dept Cell Biol Physiol & Immunol, Barcelona, Spain
Josep Carreras Leukemia Res Inst, Leukaemia Stem Cell Grp, Badalona, Spain
Leon, TE:
Univ Barcelona, Sch Biol, Dept Cell Biol Physiol & Immunol, Barcelona, Spain
UCL, UCL Canc Inst, Dept Haematol, London, England
Font-Diaz, J:
Univ Barcelona, Sch Biol, Dept Cell Biol Physiol & Immunol, Barcelona, Spain
Univ Barcelona IBUB, Inst Biomed, Barcelona, Spain
De la Rosa, JV:
Univ Las Palmas Gran Canaria, Unidad Biomed Unidad Asociada CSIC, Inst Univ Invest Biomed & Sanitarias IUIBS, Grp Invest Medio Ambiente & Salud GIMAS,ULPGC, Las Palmas Gran Canaria, Spain
Castrillo, A:
Univ Las Palmas Gran Canaria, Unidad Biomed Unidad Asociada CSIC, Inst Univ Invest Biomed & Sanitarias IUIBS, Grp Invest Medio Ambiente & Salud GIMAS,ULPGC, Las Palmas Gran Canaria, Spain
Univ Autonoma Madrid, CSIC, Inst Invest Biomed Alberto Sols, Madrid, Spain
Picard, FR:
Univ Marburg, Inst Med Microbiol & Hosp Hyg, Marburg, Germany
Staudenraus, D:
Univ Marburg, Inst Med Microbiol & Hosp Hyg, Marburg, Germany
Huber, M:
Univ Marburg, Inst Med Microbiol & Hosp Hyg, Marburg, Germany
Cedo, L:
Inst Invest Biomed IIB St Pau, Barcelona, Spain
CIBERDEM, CIBER Diabet & Enfermedades Metab Asociadas, Lhospitalet De Llobregat, Spain
Escola-Gil, JC:
Inst Invest Biomed IIB St Pau, Barcelona, Spain
CIBERDEM, CIBER Diabet & Enfermedades Metab Asociadas, Lhospitalet De Llobregat, Spain
Campos, L:
Univ Marburg, Inst Med Microbiol & Hosp Hyg, Marburg, Germany
Erasmus MC Univ Med Ctr, Dept Gastroenterol & Hepatol, Rotterdam, Netherlands
Bakiri, L:
Med Univ Vienna, Dept Lab Med, Vienna, Austria
Wagner, EF:
Med Univ Vienna, Dept Lab Med, Vienna, Austria
Med Univ Vienna, Dept Dermatol, Vienna, Austria
Caelles, C:
Univ Barcelona IBUB, Inst Biomed, Barcelona, Spain
Univ Barcelona, Dept Biochem & Physiol, Sch Pharm & Food Sci, Barcelona, Spain
Stratmann, T:
Univ Barcelona, Sch Biol, Dept Cell Biol Physiol & Immunol, Barcelona, Spain
Van Ginderachter, JA:
Vrije Univ Brussel, Lab Cellular & Mol Immunol, Brussels, Belgium
VIB Ctr Inflammat Res, Lab Myeloid Cell Immunol, Brussels, Belgium
Valledor, AF:
Univ Barcelona, Sch Biol, Dept Cell Biol Physiol & Immunol, Barcelona, Spain
Univ Barcelona IBUB, Inst Biomed, Barcelona, Spain
Green Accepted
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