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Identification of a T cell lymphoma in plkcGAPDH transgénic mice (RNA-Seq)

ABSTRACT: Glyceraldehyde-3-phosphate-dehydrogenase (GAPDH) is emerging as a key player in T-cell development, function and cancer. Here we investigated the role of GAPDH in T-cell development/function by overexpressing GAPDH in the T-cell lineage. Aged mice developed: 1) splenomegaly, 2) enlarged lymph nodes, 3) lymphocyte-infiltrations in the liver and bone marrow. All showed an increase of strongly proliferating and clonal Tfh CXCR5+PD1highCD4+-T cells associated with germinal center B cells and inflammatory cytokine-release. Gene-set-expression-analysis confirmed that this lymphoma was equivalent to human angioimmunoblastic T-cell lymphoma (AITL). Mechanistically, GAPDH induced NF-B pathway in the murine AITL in vivo inhibition of NF-B combined with anti-PD1 increased mice survival and cancer immune response. GAPDH-dependent modulation of NF-B in T-cells allowed to model AITL-disease and evaluate treatments.

ORGANISM(S): Mus musculus

PROVIDER: GSE121747 | GEO | 2021/10/20

REPOSITORIES: GEO

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Project description: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.

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Identification of a T cell lymphoma in plkcGAPDH transgénic mice (RNA-Seq)

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