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Inhibition of choline metabolism in an angioimmunoblastic T cell lymphoma preclinical model reveals a new treatment option

ABSTRACT: Background: Angioimmunoblastic T-cell lymphoma (AITL) is a malignancy with very poor survival outcome, in need of new more specific therapeutic regimen. 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, leveraged on our previously established AITL mouse model by crossing metabolomic and proteomic data of murine AITL cells. 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, respectively, are upregulated in multiple tumors other than AITL. Here we showed that treatment of our mAITL preclinical mouse model with the fatty acid oxydation inhibitor, etomoxir, significantly increased their survival and even reverted the exhausted CD8 T cells in the tumor into potent cytotoxic anti-tumor cells. Specific inhibition of Chok confirmed the importance of the phosphatidylcholine production pathway in the neoplastic CD4+ T cells, since it irradicated almost all the 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 the choline metabolism in AITL might represent a new therapeutic strategy for these patients.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Spleen, T Cell

SUBMITTER: Matteo Pecoraro

LAB HEAD: Els Verhoeyen

PROVIDER: PXD046786 | Pride | 2024-04-04

REPOSITORIES: Pride

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Publications

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

Krug Adrien A Tosolini Marie M Madji Hounoum Blandine B Fournié Jean-Jacques JJ Geiger Roger R Pecoraro Matteo M Emond Patrick P Gaulard Philippe P Lemonnier François F Ricci Jean-Ehrland JE Verhoeyen Els E

Journal of experimental & clinical cancer research : CR 20240206 1

<h4>Background</h4>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<sup>+</sup> 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.<h4>Methods</h4>To reveal the prominent metabolic p ...[more]

PMID: 38321568

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Project description:Dysregulated choline metabolism is a well-known feature of breast cancer, but the underlying mechanisms are not fully understood. In this study, the metabolomic and transcriptomic characteristics of a large panel of human breast cancer xenograft models were mapped, with focus on choline metabolism. Methods: Tumor specimens from 34 patient-derived xenograft models were collected and divided in two. One part was examined using high-resolution magic angle spinning (HR-MAS) MR spectroscopy while another part was analysed using gene expression microarrays. Expression data of genes encoding proteins in the choline metabolism pathway were analysed and correlated to the levels of choline (Cho), phosphocholine (PCho) and glycerophosphocholine (GPC) using Pearson’s correlation analysis. For comparison purposes, metabolic and gene expression data were collected from human breast tumors belonging to corresponding molecular subgroups. Results: Most of the xenograft models were classified as basal-like (N=19) or luminal B (N=7). These two subgroups showed significantly different choline metabolic and gene expression profiles. The luminal B xenografts were characterized by a high PCho/GPC ratio while the basal-like xenografts were characterized by highly variable PCho/GPC ratio. Also, Cho, PCho and GPC levels were correlated to expression of several genes encoding proteins in the choline metabolism pathway, including choline kinase alpha (CHKA) and glycerophosphodiester phosphodiesterase domain containing 5 (GDPD5). These characteristics were similar to those found in human tumor samples. Discussion: The higher PCho/GPC ratio found in luminal B compared with most basal-like breast cancer xenograft models and human tissue samples do not correspond to results observed from in vitro studies. It is likely that microenvironmental factors play a role in the in vivo regulation of choline metabolism. Cho, PCho and GPC were correlated to different choline pathway-encoding genes in luminal B compared with basal-like xenografts, suggesting that regulation of choline metabolism may vary between different breast cancer subgroups. The concordance between the metabolic and gene expression profiles from xenograft models with breast cancer tissue samples from patients indicates that these xenografts are representative models of human breast cancer and represent relevant models to study tumor metabolism in vivo. Gene expression was measured in 30 human breast cancer xenografts, one sample from each model

Dataset Information

Inhibition of choline metabolism in an angioimmunoblastic T cell lymphoma preclinical model reveals a new treatment option

Publications

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

Similar Datasets

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