4 research outputs found
Pharmacologic activation of LXR alters the expression profile of tumor-associated macrophages and the abundance of regulatory T cells in the tumor microenvironment
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.This work was supported by the following grants: Spanish Ministry of Economy and Competitivity (MINECO) grants SAF2017-89510-R and SAF2014-57856-P [to A.F. Valledor and C. Caelles; SAF2014-56819-R to A. Castrillo; SAF2017-90604-REDT and SAF2015-71878-REDT to the NuRCaMeIn network (to A.F. Valledor, C. Caelles, and A. Castrillo); Spanish Ministry of Science and Innovation (MICINN) grants SAF2011-23402 and SAF2010-14989 (to A.F. Valledor); Fundacio La Marato de TV3 grant 080930 (to A.F. Valledor); grants DFG HU 1824/5-1, 1824/7-1, and 1824/9-1 (to M. Huber); the European Cooperation in Science and Technology (COST) Action BM1404 Mye-EUNITER (http://www.mye-euniter. eu/; to A.F. Valledor, J.A. Van Ginderachter); and Instituto de Salud Carlos III and FEDER “Una manera de hacer Europa” grant FIS 16/00139 (to J.C. Escola-Gil). CIBERDEM is an Instituto de Salud Carlos III project. J.M. C received a fellowship from the University of Barcelona (APIF) and J. Font-Díaz received a fellowship
from the Spanish Ministry of Science, Innovation and Universities (FPI, PRE2018-085579)
Identifizierung funktioneller Untereinheiten des Transkriptionsfaktors interferon regulatory factor 4
Interferon regulatory factor 4 is a crucial factor in adaptive immunity in both T and B cell
mediated processes. Knockout mice lacking IRF4 show severe defects in developing
functional T cell subsets, including Th2, Th9 and Th17, as well as B cells arrested in early
development stages, which leads to absence of IgM in the serum. In T cells, IRF4 serves as
an initiation factor conveying TCR signals, priming cells for proliferation and inducing
master transcriptional regulators such as GATA3, T-bet and RORγt. To fulfil this central
role, interaction with several partners is required, among them BATF and PU.1. We
hypothesize that through precise alterations in IRF4, its functionality can be altered to
achieve selective modification of its immunoregulatory effects. Based on literature results
from binding assays, structural analysis and recurring mutations in cancer patients, we tested
many point mutations in IRF4 for their functionality in Th2, Th9 and Th17 differentiation.
Several mutations show immunomodulatory potential. Most prominent among them is
L116R, which induces Th9 differentiation and IL-9 production in Th2 cells, while at the
same time reducing Th2 and Th17 differentiation. Further, we could show that autoinhibition
of IRF4 is differentially affecting helper T cell subtypes, acting much stronger on Th9 and
Th17 cells compared to Th2 differentiated cells. In addition, tumors emerging in old IRF4
knockout mice allowed us to further study leukemogenesis and B cell development in the
context of IRF4 deficiency, leading to a disease similar to human Ph-like B-ALL. Treatment
of this disease with the JAK inhibitor Ruxolitinib increased survival by reducing blast
infiltration in the central nervous system and solid organs.
Here we show that immunomodulation via point mutations is possible and that IRF4 has
subdomains that differentially affect helper T cell subtypes, further scrutinize the effects of
autoinhibition in IRF4 and establish a potential mouse model for human Ph-like B-ALL
Interferon regulatory factor 4 plays a pivotal role in the development of aGVHD-associated colitis
ABSTRACTInterferon regulatory factor 4 (IRF4) is a master transcription factor that regulates T helper cell (Th) differentiation. It interacts with the Basic leucine zipper transcription factor, ATF-like (BATF), depletion of which in CD4+ T cells abrogates acute graft-versus-host disease (aGVHD)-induced colitis. Here, we investigated the immune-regulatory role of Irf4 in a mouse model of MHC-mismatched bone marrow transplantation. We found that recipients of allogenic Irf4-/- CD4+ T cells developed less GVHD-related symptoms. Transcriptome analysis of re-isolated donor Irf4-/- CD4+ T helper (Th) cells, revealed gene expression profiles consistent with loss of effector T helper cell signatures and enrichment of a regulatory T cell (Treg) gene expression signature. In line with these findings, we observed a high expression of the transcription factor BTB and CNC homolog 2; (BACH2) in Irf4-/- T cells, which is associated with the formation of Treg cells and suppression of Th subset differentiation. We also found an association between BACH2 expression and Treg differentiation in patients with intestinal GVHD. Finally, our results indicate that IRF4 and BACH2 act as counterparts in Th cell polarization and immune homeostasis during GVHD. In conclusion, targeting the BACH2/IRF4-axis could help to develop novel therapeutic approaches against GVHD