Raccosta, Laura and Marinozzi, Maura and Costantini, Susan and Maggioni, Daniela and Ferreira, Lorena Maria and Corna, Gianfranca and Zordan, Paola and Sorice, Angela and Farinello, Diego and Bianchessi, Silvia and Riba, Michela and Lazarevic, Dejan and Provero, Paolo and Mack, Matthias and Bondanza, Attilio and Nalvarte, Ivan and Gustafsson, J-A and Ranzani, Valeria and De Sanctis, Francesco and Ugel, Stefano and Baron, Silvere and Lobaccaro, Jean-Marc A. and Pontini, Lorenzo and Pacciarini, Manuela and Traversari, Catia and Pagani, Massimiliano and Bronte, Vincenzo and Sitia, Giovanni and Antonson, Per and Brendolan, Andrea and Budillon, Alfredo and Russo, Vincenzo (2023) Harnessing the reverse cholesterol transport pathway to favor differentiation of monocyte-derived APCs and antitumor responses. CELL DEATH & DISEASE, 14 (2): 129. ISSN 2041-4889,
Full text not available from this repository. (Request a copy)Abstract
Lipid 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ANTIGEN-PRESENTING CELLS; DENDRITIC CELLS; SIGNALING PATHWAY; IMMUNOTHERAPY; RECRUITMENT; LXR; MACROPHAGES; METABOLISM; ACTIVATION; MECHANISMS; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Abteilung für Nephrologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 30 Jan 2024 12:37 |
| Last Modified: | 30 Jan 2024 12:37 |
| URI: | https://pred.uni-regensburg.de/id/eprint/60870 |
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