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Identification of a neoplastic Tfh-like cellular subset in a mouse model of angioimmunoblastic T cell lymphoma (AITL)

ABSTRACT: Nodal T-follicular helper cell lymphoma, angioimmunoblastic type (nTFHL-AI, or AITL), is an aggressive peripheral T cell lymphoma without effective treatments. It has been shown that genetic and epigenetic changes lead to the expansion of neoplastic CD4+ T cells originating from T follicular helper (Tfh) cells, which subsequently cause B cell expansion and tumor. However, it remains unclear if the Tfh-like cell populations contain a subset that drive tumor progression and, if so, whether such a subset may have druggable targets. Using a mouse model of AITL driven by heterozygous sanroque mutation (Roquinsan/+), we identified a tumor-enriched Tfh cell subset highly expressing CXCR6 and IL-18 receptor, termed “Double-Expressor (DE) Tfh” cells. DE Tfh cells also expressed higher levels of enhancer of zeste homolog 2 (EZH2). In vitro data indicated that IL-18 and EZH2 are required for the proliferation of DE Tfh cells. Furthermore, DE Tfh cells have a potent capacity to expand B cells when adoptively transferred to lymphopenic recipients. On the other hand, depletion of DE Tfh cells via Ezh2 gene deletion, inhibition of EZH2 (using FDA-approved drug, tazemetostat), or anti-CXCR6 mAb led to tumor regression. These findings may be relevant to a subset of AITL cases since we found that ~20-30% of AITL patient samples have concomittantly elevated expression of CXCR6, IL-18R1, and IFNG. Thus, our study identified a pathogenic Tfh-like subset essential for AITL tumor progression in a mouse model and suggests that identifying and targeting DE Tfh-like subset in AITL patients might be an effective strategy.

ORGANISM(S): Mus musculus

PROVIDER: GSE303738 | GEO | 2026/01/07

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 neoplastic Tfh-like cellular subset in a mouse model of angioimmunoblastic T cell lymphoma (AITL)

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