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

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 In this experiment we analized the effect of RGX104 treatment on transcriptome of M2 generated in vitro from ThP1 cell lines. ThP1 were polarized toward M2 with PMA (320nM) fron six hours and IL-4 and IL-13 (20ng/µl each) for the last 18 hours. Then, cells were eicther treated with DMSO (control) and RGX104 (2μM) for 24 hours in a 3D cell culture system (Alvetex). RNA was extracted and gene expresion profiling performed.