1. CD8+ T-cell differentiation and dysfunction inform treatment response in acute myeloid leukemia.
- Author
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Mazziotta F, Biavati L, Rimando J, Rutella S, Borcherding N, Parbhoo S, Mukhopadhyay R, Chowdhury S, Knaus HA, Valent P, Hackl H, Borrello IM, Blazar BR, Hatzi K, Gojo I, and Luznik L
- Subjects
- Humans, Single-Cell Analysis, Immunologic Memory, Male, Female, Cellular Senescence, Treatment Outcome, Leukemia, Myeloid, Acute pathology, Leukemia, Myeloid, Acute immunology, Leukemia, Myeloid, Acute therapy, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes pathology, Cell Differentiation
- Abstract
Abstract: The interplay between T-cell states of differentiation, dysfunction, and treatment response in acute myeloid leukemia (AML) remains unclear. Here, we leveraged a multimodal approach encompassing high-dimensional flow cytometry and single-cell transcriptomics and found that early memory CD8+ T cells are associated with therapy response and exhibit a bifurcation into 2 distinct terminal end states. One state is enriched for markers of activation, whereas the other expresses natural killer (NK)-like and senescence markers. The skewed clonal differentiation trajectory toward CD8+ senescence was also a hallmark indicative of therapy resistance. We validated these findings by generating an AML CD8+ single-cell atlas integrating our data and other independent data sets. Finally, our analysis revealed that an imbalance between CD8+ early memory and senescent-like cells is linked to AML treatment refractoriness and poor survival. Our study provides crucial insights into the dynamics of CD8+ T-cell differentiation and advances our understanding of CD8+ T-cell dysfunction in AML., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
- Published
- 2024
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