Inhibition of choline metabolism in an angioimmunoblastic T-cell lymphoma preclinical model reveals a new metabolic vulnerability as possible target for treatment
Abstract 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 n...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-02-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-024-02952-w |
| _version_ | 1797272730651852800 |
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| author | Adrien Krug Marie Tosolini Blandine Madji Hounoum Jean-Jacques Fournié Roger Geiger Matteo Pecoraro Patrick Emond Philippe Gaulard François Lemonnier Jean-Ehrland Ricci Els Verhoeyen |
| author_facet | Adrien Krug Marie Tosolini Blandine Madji Hounoum Jean-Jacques Fournié Roger Geiger Matteo Pecoraro Patrick Emond Philippe Gaulard François Lemonnier Jean-Ehrland Ricci Els Verhoeyen |
| author_sort | Adrien Krug |
| collection | DOAJ |
| description | Abstract 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-1high 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. |
| first_indexed | 2024-03-07T14:34:31Z |
| format | Article |
| id | doaj.art-0685f8cd030f49b99d2ba6536610e7de |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-03-07T14:34:31Z |
| publishDate | 2024-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-0685f8cd030f49b99d2ba6536610e7de2024-03-05T20:43:35ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662024-02-0143112010.1186/s13046-024-02952-wInhibition of choline metabolism in an angioimmunoblastic T-cell lymphoma preclinical model reveals a new metabolic vulnerability as possible target for treatmentAdrien Krug0Marie Tosolini1Blandine Madji Hounoum2Jean-Jacques Fournié3Roger Geiger4Matteo Pecoraro5Patrick Emond6Philippe Gaulard7François Lemonnier8Jean-Ehrland Ricci9Els Verhoeyen10Université Côte d’Azur, INSERMCentre de Recherches en Cancérologie de Toulouse, CRCT, Université de Toulouse, CNRS, Université Toulouse III-Paul Sabatier, InsermUniversité Côte d’Azur, INSERMCentre de Recherches en Cancérologie de Toulouse, CRCT, Université de Toulouse, CNRS, Université Toulouse III-Paul Sabatier, InsermInstitute for Research in Biomedicine (IRB), Università della Svizzera italianaInstitute for Research in Biomedicine (IRB), Università della Svizzera italianaUMR iBrain, Université de ToursUniversité Paris-Est Créteil, Institut Mondor de Recherche BiomedicaleUniversité Paris-Est Créteil, Institut Mondor de Recherche BiomedicaleUniversité Côte d’Azur, INSERMUniversité Côte d’Azur, INSERMAbstract 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-1high 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.https://doi.org/10.1186/s13046-024-02952-wCholineAITLLipid metabolismCDP-choline pathwayCDP-ethanolamine pathwayCholine kinase |
| spellingShingle | Adrien Krug Marie Tosolini Blandine Madji Hounoum Jean-Jacques Fournié Roger Geiger Matteo Pecoraro Patrick Emond Philippe Gaulard François Lemonnier Jean-Ehrland Ricci Els Verhoeyen Inhibition of choline metabolism in an angioimmunoblastic T-cell lymphoma preclinical model reveals a new metabolic vulnerability as possible target for treatment Journal of Experimental & Clinical Cancer Research Choline AITL Lipid metabolism CDP-choline pathway CDP-ethanolamine pathway Choline kinase |
| title | Inhibition of choline metabolism in an angioimmunoblastic T-cell lymphoma preclinical model reveals a new metabolic vulnerability as possible target for treatment |
| title_full | Inhibition of choline metabolism in an angioimmunoblastic T-cell lymphoma preclinical model reveals a new metabolic vulnerability as possible target for treatment |
| title_fullStr | Inhibition of choline metabolism in an angioimmunoblastic T-cell lymphoma preclinical model reveals a new metabolic vulnerability as possible target for treatment |
| title_full_unstemmed | Inhibition of choline metabolism in an angioimmunoblastic T-cell lymphoma preclinical model reveals a new metabolic vulnerability as possible target for treatment |
| title_short | Inhibition of choline metabolism in an angioimmunoblastic T-cell lymphoma preclinical model reveals a new metabolic vulnerability as possible target for treatment |
| title_sort | inhibition of choline metabolism in an angioimmunoblastic t cell lymphoma preclinical model reveals a new metabolic vulnerability as possible target for treatment |
| topic | Choline AITL Lipid metabolism CDP-choline pathway CDP-ethanolamine pathway Choline kinase |
| url | https://doi.org/10.1186/s13046-024-02952-w |
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