Inhibition of choline metabolism in an angioimmunoblastic T-cell lymphoma preclinical model reveals a new metabolic vulnerability as possible target for treatment.

Autor: Krug A; Université Côte d'Azur, INSERM, C3M, 06204, Nice, France.; Equipe Labellisée Ligue Contre Le Cancer, 06204, Nice, France., Tosolini M; Centre de Recherches en Cancérologie de Toulouse, CRCT, Université de Toulouse, CNRS, Université Toulouse III-Paul Sabatier, Inserm, Toulouse, France., Madji Hounoum B; Université Côte d'Azur, INSERM, C3M, 06204, Nice, France.; Equipe Labellisée Ligue Contre Le Cancer, 06204, Nice, France., Fournié JJ; Centre de Recherches en Cancérologie de Toulouse, CRCT, Université de Toulouse, CNRS, Université Toulouse III-Paul Sabatier, Inserm, Toulouse, France.; Labex TOUCAN, Toulouse, France., Geiger R; Institute for Research in Biomedicine (IRB), Università della Svizzera italiana, Bellinzona, Switzerland.; Institute of Oncology Research (IOR), Università della Svizzera Italiana, Bellinzona, Switzerland., Pecoraro M; Institute for Research in Biomedicine (IRB), Università della Svizzera italiana, Bellinzona, Switzerland., Emond P; UMR iBrain, Université de Tours, Inserm, Tours, France., Gaulard P; Université Paris-Est Créteil, Institut Mondor de Recherche Biomedicale, Creteil, INSERMU955, France.; AP-HP, Groupe Hospitalo-Universitaire Chenevier Mondor, Département de Pathologie, 94010, Créteil, France., Lemonnier F; Université Paris-Est Créteil, Institut Mondor de Recherche Biomedicale, Creteil, INSERMU955, France.; AP-HP, Groupe Hospitalo-Universitaire Chenevier Mondor, Service Unité Hémopathies Lymphoides, 94010, Créteil, France., Ricci JE; Université Côte d'Azur, INSERM, C3M, 06204, Nice, France.; Equipe Labellisée Ligue Contre Le Cancer, 06204, Nice, France., Verhoeyen E; Université Côte d'Azur, INSERM, C3M, 06204, Nice, France. els.verhoeyen@unice.fr.; Equipe Labellisée Ligue Contre Le Cancer, 06204, Nice, France. els.verhoeyen@unice.fr.; CIRI, Université de Lyon, INSERM U1111, ENS de Lyon, University Lyon1, CNRS, UMR5308, Lyon, 69007, France. els.verhoeyen@unice.fr.
Jazyk: angličtina
Zdroj: Journal of experimental & clinical cancer research : CR [J Exp Clin Cancer Res] 2024 Feb 06; Vol. 43 (1), pp. 43. Date of Electronic Publication: 2024 Feb 06.
DOI: 10.1186/s13046-024-02952-w
Abstrakt: Background: Angioimmunoblastic T-cell lymphoma (AITL) is a malignancy with very poor survival outcome, in urgent need of more specific therapeutic strategies. The drivers of malignancy in this disease are CD4 + follicular helper T cells (Tfh). The metabolism of these malignant Tfh cells was not yet elucidated. Therefore, we decided to identify their metabolic requirements with the objective to propose a novel therapeutic option.
Methods: To reveal the prominent metabolic pathways used by the AITL lymphoma cells, we relied on metabolomic and proteomic analysis of murine AITL (mAITL) T cells isolated from our established mAITL model. We confirmed these results using AITL patient and healthy T cell expression data.
Results: Strikingly, the mAITL Tfh cells were highly dependent on the second branch of the Kennedy pathway, the choline lipid pathway, responsible for the production of the major membrane constituent phosphatidylcholine. Moreover, gene expression data from Tfh cells isolated from AITL patient tumors, confirmed the upregulation of the choline lipid pathway. Several enzymes involved in this pathway such as choline kinase, catalyzing the first step in the phosphatidylcholine pathway, are upregulated in multiple tumors other than AITL. Here we showed that treatment of our mAITL preclinical mouse model with a fatty acid oxydation inhibitor, significantly increased their survival and even reverted the exhausted CD8 T cells in the tumor into potent cytotoxic anti-tumor cells. Specific inhibition of Chokα confirmed the importance of the phosphatidylcholine production pathway in neoplastic CD4 + T cells, nearly eradicating mAITL Tfh cells from the tumors. Finally, the same inhibitor induced in human AITL lymphoma biopsies cell death of the majority of the hAITL PD-1 high neoplastic cells.
Conclusion: Our results suggest that interfering with choline metabolism in AITL reveals a specific metabolic vulnerability and might represent a new therapeutic strategy for these patients.
(© 2024. The Author(s).)
Databáze: MEDLINE
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