Lysosomal damage due to cholesterol accumulation triggers immunogenic cell death

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Abstract
Cholesterol serves as a vital lipid that regulates numerous physiological processes. Nonetheless, its role in regulating cell death processes remains incompletely understood. In this study, we investigated the role of cholesterol trafficking in immunogenic cell death. Through cell-based drug screening, we identified two antidepressants, sertraline and indatraline, as potent inducers of the nuclear translocation of TFEB (transcription factor EB). Activation of TFEB was mediated through the autophagy-independent lipidation of MAP1LC3/LC3 (microtubule associated protein 1 light chain 3). Both compounds promoted cholesterol accumulation within lysosomes, resulting in lysosomal membrane permeabilization, disruption of autophagy and cell death that could be reversed by cholesterol depletion. Molecular docking analysis indicated that sertraline and indatraline have the potential to inhibit cholesterol binding to the lysosomal cholesterol transporters, NPC1 (NPC intracellular cholesterol transporter 1) and NPC2. This inhibitory effect might be further enhanced by the upregulation of NPC1 and NPC2 expression by TFEB. Both antidepressants also upregulated PLA2G15 (phospholipase A2 group XV), an enzyme that elevates lysosomal cholesterol. In cancer cells, sertraline and indatraline elicited immunogenic cell death, converting dying cells into prophylactic vaccines that were able to confer protection against tumor growth in mice. In a therapeutic setting, a single dose of each compound was sufficient to significantly reduce the outgrowth of established tumors in a T-cell-dependent manner. These results identify sertraline and indatraline as immunostimulatory agents for cancer treatment. More generally, this research shed light on novel therapeutic avenues harnessing lysosomal cholesterol transport to regulate immunogenic cell death.
Funding Information
  • Agence Nationale de la Recherche (ANR-19-CE15-0013)
  • Agence Nationale de la Recherche (ANR-23-CE13-0013-0)
  • Agence Nationale de la Recherche (ANR-21-CE44-0016)
  • Agence Nationale de la Recherche (AMMICA US23/CNRS UMS3655)
  • Association pour la Recherche sur le Cancer
  • Cancer Research ASPIRE
  • Cancéropôle Ile-de-France
  • Consejo Nacional de Ciencia y Tecnología de México (757821)
  • Equipex Onco-Pheno-Screen
  • European Joint Programme on Rare Diseases
  • European Union Horizon 2020 Projects Oncobiome and Crimson
  • Fondation Carrefour
  • Fondation pour la Recherche Médicale
  • Gustave Roussy Odyssea
  • IdEx Université de Paris (ANR-18-IDEX-0001)
  • Institut National de la Santé et de la Recherche Médicale
  • Institut National Du Cancer (PLBIO23–216)
  • Inca (PLBIO22–101)
  • Institut Universitaire de France
  • Labex Immuno-Oncology (ANR-18-IDEX-0001)
  • Ligue Contre le Cancer
  • Ligue Contre le Cancer (IP/SC-17519)
  • Seerave Foundation
  • SIRIC Cancer Research and Personalized Medicine
  • SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination
  • Taxe d’apprentissage (IGR KAAL-2022)
  • RHU Immunolife

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