Cell Death and Disease (Feb 2023)

Harnessing the reverse cholesterol transport pathway to favor differentiation of monocyte-derived APCs and antitumor responses

  • Laura Raccosta,
  • Maura Marinozzi,
  • Susan Costantini,
  • Daniela Maggioni,
  • Lorena Maria Ferreira,
  • Gianfranca Corna,
  • Paola Zordan,
  • Angela Sorice,
  • Diego Farinello,
  • Silvia Bianchessi,
  • Michela Riba,
  • Dejan Lazarevic,
  • Paolo Provero,
  • Matthias Mack,
  • Attilio Bondanza,
  • Ivan Nalvarte,
  • J-A Gustafsson,
  • Valeria Ranzani,
  • Francesco De Sanctis,
  • Stefano Ugel,
  • Silvère Baron,
  • Jean-Marc A. Lobaccaro,
  • Lorenzo Pontini,
  • Manuela Pacciarini,
  • Catia Traversari,
  • Massimiliano Pagani,
  • Vincenzo Bronte,
  • Giovanni Sitia,
  • Per Antonson,
  • Andrea Brendolan,
  • Alfredo Budillon,
  • Vincenzo Russo

DOI
https://doi.org/10.1038/s41419-023-05620-7
Journal volume & issue
Vol. 14, no. 2
pp. 1 – 21

Abstract

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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.