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NR1H3 (LXRα) IS ASSOCIATED WITH PRO-INFLAMMATORY MACROPHAGES, PREDICTS SURVIVAL AND PROVIDES RATIONALE FOR NEW IMMUNOMODULATION IN DIFFUSE LARGE B-CELL LYMPHOMA

ABSTRACT: The role of macrophages (Mo) and their prognostic impact in diffuse large B-cell lymphomas (DLBCL) remain controversial. By regulating the lipid metabolism, Liver-X-receptors (LXRs) control Mo polarization/inflammatory response, and their pharmacological modulation is under clinical investigation to treat human cancers, including lymphomas. Herein, we surveyed the role of LXRs in DLBCL for potential prognostic and therapeutic purposes. By comparing bulk tumors with purified malignant and normal B-cells, we found an intriguing association of NR1H3, encoding for the LXR-α isoform, with the tumor microenvironment (TME). CIBERSORTx-based purification on large DLBCL datasets revealed a high expression of the receptor in M1-like pro-inflammatory Mo. By determining an expression cut-off of NR1H3, we used digital-expression to validate its prognostic capacity on two large independent on-trial and real-world cohorts. Independently of classical prognosticators, NR1H3high patients displayed longer survival compared to NR1H3low cases and, a high-resolution Mo GEP dissection suggested a remarkable transcriptional divergence between subgroups. Finally, treating in vitro generated M2 Mo, that display basal low NR1H3, with a new oral LXR agonist, we observed significant upregulation of NR1H3 along with inflammatory genes. Overall, our findings indicate NR1H3 as a biomarker of Mo in DLBCL, useful to identify patients at different risk and heterogenous TME who could benefit from Mo-directed immunomodulation in DLBCL. Expression data from in vitro generated macrophages from ThP1 treated either with DMSO or RGX104

ORGANISM(S): Homo sapiens

PROVIDER: GSE195651 | GEO | 2022/05/31

REPOSITORIES: GEO

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Project description:The objective of the study was to figure out the impact of LXR signaling on human macrophages. Primary human macrophages in an early differentiating and a mature differentiation state were treated with the LXR agonist T091317 for 4 and 24 h and transcriptome-wide expression analysis were performed. As LXRa is highly induced during macrophage differentiation and 68% of all LXRs targets change their expression during this process, we suggest that LXRs have essential functions in macrophage development. More than 238 genes are regulated in early as well as mature macrophages by activation of LXRs; most of them are up-regulated. LXRs administrate differentiation state specific as well as common macrophages functions related primarily to lipid homeostasis, immune response and cell fate. Interestingly, almost only genes related to lipid and cholesterol metabolism are overrepresented among early induced genes, whereas genes related to immune functions respond later, implying the existence of indirect mechanisms of control. Furthermore, in early differentiating macrophages cell proliferation and cell death associated genes are induced after 24 h of LXR activation, whereas in mature macrophages, showing high LXRa expression, the same functional cluster respond far earlier (4 h) after LXR ligand treatment. In conclusion, our data suggest that LXRs are modulators of macrophage differentiation, operating principally as positive transcriptional regulators of genes involved in lipid and cholesterol metabolism and by this indirectly influencing the immunophenotype of macrophages. CD14 positive cells of healthy donors were isolated by magnetic separation and differentiated in the presence of human serum to macrophages. At an early differentiating state (16 h after isolation) and at in mature differentiating state (day 11 after isolation) the cells were treated with the synthetical LXR agonist T091317 respective its solvent DMSO for 4 and 24 h. RNA was isolated and a whole genome microarray was performed.

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NR1H3 (LXRα) IS ASSOCIATED WITH PRO-INFLAMMATORY MACROPHAGES, PREDICTS SURVIVAL AND PROVIDES RATIONALE FOR NEW IMMUNOMODULATION IN DIFFUSE LARGE B-CELL LYMPHOMA

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