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Integration analysis reveal De Novo Angioimmunoblastic T Cell Lymphoma with Virus Responsive CD8+ T cell Features

ABSTRACT: AITL usually consists of a small population of malignant T cells extensively infiltrated by multiple lineages of other immune cells. It is challenging to characterize the tumour cells with traditional histopathology or next-generation sequencing technique using bulk tumour. However, the recent advances in single-cell sequencing technologies have enabled scientists to dissect cellular heterogeneity and gain new insights into cell origins and tumorigenesis of various hematologic malignancy5-8. In this study, we holistically analysis a typical case of AITL tumour using single-cell profiling, including CITE-Seq and immune repertoire sequencing on the same cell. The integration analysis revealed that the neoplastic cells are more similar to CD8+ cytotoxic T cells instead of Tfh cells. Moreover, we further confirmed that GAPDH-activated NFκB pathway was the key driver pathway on tumorigenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE197188 | GEO | 2022/02/25

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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Integration analysis reveal De Novo Angioimmunoblastic T Cell Lymphoma with Virus Responsive CD8+ T cell Features

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