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Single-cell RNA sequencing reveals acquisition of a FOXP3-positive regulatory-like state in relapsed TFH lymphoma

ABSTRACT: Nodal T follicular helper cell lymphomas (nTFHLs) are mature T-cell neoplasms characterized by transcriptional and phenotypic features of TFH cells. In this study, we analyzed relapsed TFH lymphoma samples using single-cell RNA sequencing, TCR repertoire analysis, whole-exome sequencing, and viral detection analysis. Single-cell transcriptomic profiling identified a dominant malignant T-cell population expressing canonical TFH-associated genes, with acquisition of a FOXP3-positive regulatory-like transcriptional state at relapse. T-cell receptor clonotype analysis demonstrated oligoclonal expansion within the malignant compartment. Targeted genomic profiling identified recurrent TET2 mutations together with PLCG1 and TP53 alterations. Viral detection analysis identified EBV sequences but no HTLV-1/2 sequences. Processed Seurat objects, cell-level metadata, mutation annotation tables, and viral detection results are provided.

ORGANISM(S): Homo sapiens

PROVIDER: GSE332984 | GEO | 2026/05/22

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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Single-cell RNA sequencing reveals acquisition of a FOXP3-positive regulatory-like state in relapsed TFH lymphoma

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