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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 prognostic purposes. Comparing bulk tumors with purified malignant and normal B-cells, we found an intriguing association of NR1H3, encoding for the LXRisoform, with the tumor microenvironment (TME). CIBERSORTx-based purification on large DLBCL datasets revealed a high expression of the receptor transcript in M1-like pro-inflammatory Mo. By determining an expression cut-off of NR1H3, we used digital measurement 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 with NR1H3low cases and a high-resolution Mo GEP dissection suggested a remarkable transcriptional divergence between subgroups. Overall, our findings indicate NR1H3 as a Mo-related biomarker identifying patients at higher risk and prompt future preclinical studies investigating its mouldability for therapeutic purposes. © 2022 The Authors. Hematological Oncology published by John Wiley & Sons Ltd.


Maria Carmela Vegliante, Saveria Mazzara, Gian Maria Zaccaria, Simona De Summa, Flavia Esposito, Federica Melle, Giovanna Motta, Maria Rosaria Sapienza, Giuseppina Opinto, Giacomo Volpe, Antonella Bucci, Grazia Gargano, Anna Enjuanes, Valentina Tabanelli, Stefano Fiori, Carla Minoia, Felice Clemente, Antonio Negri, Alessandro Gulino, Gaia Morello, Anna Scattone, Alfredo F Zito, Stefania Tommasi, Claudio Agostinelli, Umberto Vitolo, Annalisa Chiappella, Anna Maria Barbui, Enrico Derenzini, Pier Luigi Zinzani, Beatrice Casadei, Alfredo Rivas-Delgado, Armando López-Guillermo, Elias Campo, Antonio Moschetta, Attilio Guarini, Stefano A Pileri, Sabino Ciavarella. NR1H3 (LXRα) is associated with pro-inflammatory macrophages, predicts survival and suggests potential therapeutic rationales in diffuse large b-cell lymphoma. Hematological oncology. 2022 Dec;40(5):864-875

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PMID: 35850118

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