Harnessing the reverse cholesterol transport pathway to favor differentiation of monocyte-derived APCs and antitumor responses
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Published:2023-02-15
Issue:2
Volume:14
Page:
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ISSN:2041-4889
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Container-title:Cell Death & Disease
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language:en
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Short-container-title:Cell Death Dis
Author:
Raccosta Laura, Marinozzi MauraORCID, Costantini Susan, Maggioni Daniela, Ferreira Lorena Maria, Corna Gianfranca, Zordan Paola, Sorice Angela, Farinello Diego, Bianchessi Silvia, Riba Michela, Lazarevic DejanORCID, Provero Paolo, Mack MatthiasORCID, Bondanza Attilio, Nalvarte IvanORCID, Gustafsson J-A, Ranzani Valeria, De Sanctis Francesco, Ugel StefanoORCID, Baron Silvère, Lobaccaro Jean-Marc A., Pontini Lorenzo, Pacciarini Manuela, Traversari Catia, Pagani Massimiliano, Bronte VincenzoORCID, Sitia GiovanniORCID, Antonson Per, Brendolan Andrea, Budillon AlfredoORCID, Russo VincenzoORCID
Abstract
AbstractLipid and cholesterol metabolism play a crucial role in tumor cell behavior and in shaping the tumor microenvironment. In particular, enzymatic and non-enzymatic cholesterol metabolism, and derived metabolites control dendritic cell (DC) functions, ultimately impacting tumor antigen presentation within and outside the tumor mass, dampening tumor immunity and immunotherapeutic attempts. The mechanisms accounting for such events remain largely to be defined. Here we perturbed (oxy)sterol metabolism genetically and pharmacologically and analyzed the tumor lipidome landscape in relation to the tumor-infiltrating immune cells. We report that perturbing the lipidome of tumor microenvironment by the expression of sulfotransferase 2B1b crucial in cholesterol and oxysterol sulfate synthesis, favored intratumoral representation of monocyte-derived antigen-presenting cells, including monocyte-DCs. We also found that treating mice with a newly developed antagonist of the oxysterol receptors Liver X Receptors (LXRs), promoted intratumoral monocyte-DC differentiation, delayed tumor growth and synergized with anti-PD-1 immunotherapy and adoptive T cell therapy. Of note, looking at LXR/cholesterol gene signature in melanoma patients treated with anti-PD-1-based immunotherapy predicted diverse clinical outcomes. Indeed, patients whose tumors were poorly infiltrated by monocytes/macrophages expressing LXR target genes showed improved survival over the course of therapy. Thus, our data support a role for (oxy)sterol metabolism in shaping monocyte-to-DC differentiation, and in tumor antigen presentation critical for responsiveness to immunotherapy. The identification of a new LXR antagonist opens new treatment avenues for cancer patients.
Funder
Fondazione Umberto Veronesi Associazione Italiana per la Ricerca sul Cancro
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Cell Biology,Cellular and Molecular Neuroscience,Immunology
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