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Effect of Ibrutinib on the gene expression of CD4+ cells from patients with Peripheral T-cell lymphoma (PTCL)

ABSTRACT: Interleukin-2-inducible T-cell kinase (ITK) has essential roles in T-cell proliferation in response to T-cell receptor stimulation and promotes Th2 and Th17 cell differentiation while suppressing Treg differentiation. ITK inhibitors have not previously been investigated for their ability to modify differentiation of either normal or malignant human CD4+ T-cells. We demonstrate that normal tonsillar CD4+ T-cell differentiation to Tfh and Th17 cells is inhibited by ITK inhibitors (ITKi) while Treg differentiation is promoted. Purified CD4+ T-cells from two cases of peripheral T-cell lymphoma demonstrated the capacity to proliferate and differentiate to Tfh, Th17 or Treg subsets in vitro. Gene expression profiling showed differences in Th-cell signature genes between normal and lymphoma cells. ITKi promoted Treg differentiation while suppressing Tfh and Th17 differentiation. The majority of CD4+ T-cells within lymph node sections did not express BCL6 compatible with the in vitro results being due to differentiation and not outgrowth already differentiated populations. The novel concept suggested by this report is that some cases of PTCL-NOS show a capacity to differentiate, which can be modified by ITKi for potential therapeutic benefit.

ORGANISM(S): Homo sapiens

PROVIDER: GSE120403 | GEO | 2018/09/26

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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Effect of Ibrutinib on the gene expression of CD4+ cells from patients with Peripheral T-cell lymphoma (PTCL)

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