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LYMPHOMA

High-dimensional and single-cell transcriptome analysis of the tumor microenvironment in angioimmunoblastic T cell lymphoma (AITL)

Abstract

Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive lymphoid malignancy associated with a poor clinical prognosis. The AITL tumor microenvironment (TME) is unique, featuring a minority population of malignant CD4+ T follicular helper (TFH) cells inter-mixed with a diverse infiltrate of multi-lineage immune cells. While much of the understanding of AITL biology to date has focused on characteristics of the malignant clone, less is known about the many non-malignant populations that comprise the TME. Recently, mutational consistencies have been identified between malignant cells and non-malignant B cells within the AITL TME. As a result, a significant role for non-malignant populations in AITL biology has been increasingly hypothesized. In this study, we have utilized mass cytometry and single-cell transcriptome analysis to identify several expanded populations within the AITL TME. Notably, we find that B cells within the AITL TME feature decreased expression of key markers including CD73 and CXCR5. Furthermore, we describe the expansion of distinct CD8+ T cell populations that feature an exhausted phenotype and an underlying expression profile indicative of dysfunction, impaired cytotoxicity, and upregulation of the chemokines XCL2 and XCL1.

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Fig. 1: AITL tumor microenvironment features CD8+ expansion, global shift in B cell phenotypes.
Fig. 2: CD4+ populations in the AITL TME.
Fig. 3: Global shift in AITL B cells marked by loss of CD73, CXCR5.
Fig. 4: Expansion of distinct CD8+ T cell populations within the AITL TME.
Fig. 5: Defining the RNA transcriptome of expanded CD8+ populations in AITL.
Fig. 6: Immunoblasts and NK cell populations in AITL.

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Acknowledgements

The authors acknowledge grant funding in support of this work from the Leukemia & Lymphoma Society (LLS), the National Institutes of Health (P50 CA97274), and the Predolin Foundation.

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Correspondence to Stephen M. Ansell.

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For JRC research funding provided by NanoString and BMS/Celgene. For SMA, research funding provided by Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Trillium and Takeda. The remaining authors report nothing to disclose.

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Pritchett, J.C., Yang, ZZ., Kim, H.J. et al. High-dimensional and single-cell transcriptome analysis of the tumor microenvironment in angioimmunoblastic T cell lymphoma (AITL). Leukemia 36, 165–176 (2022). https://doi.org/10.1038/s41375-021-01321-2

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