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The remission status of AML patients after allo-HCT is associated with a distinct single-cell bone marrow T-cell signature

Acute myeloid leukemia (AML) is a hematologic malignancy for which allogeneic hematopoietic cell transplantation (allo-HCT) often remains the only curative therapeutic approach. However, incapability of T cells to recognize and eliminate residual leukemia stem cells might lead to an insufficient gra...

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Hauptverfasser: Mathioudaki, Anna (VerfasserIn) , Wang, Xizhe (VerfasserIn) , Sedloev, David (VerfasserIn) , Huth, Richard (VerfasserIn) , Kamal, Aryan (VerfasserIn) , Hundemer, Michael (VerfasserIn) , Liu, Yi (VerfasserIn) , Vasileiou, Spyridoula (VerfasserIn) , Lulla, Premal (VerfasserIn) , Müller-Tidow, Carsten (VerfasserIn) , Dreger, Peter (VerfasserIn) , Luft, Thomas (VerfasserIn) , Sauer, Tim (VerfasserIn) , Schmitt, Michael (VerfasserIn) , Zaugg, Judith B. (VerfasserIn) , Pabst, Caroline (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: March 28 2024
In: Blood
Year: 2024, Jahrgang: 143, Heft: 13, Pages: 1269-1281
ISSN:1528-0020
DOI:10.1182/blood.2023021815
Online-Zugang:lizenzpflichtig
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Verfasserangaben:Anna Mathioudaki, Xizhe Wang, David Sedloev, Richard Huth, Aryan Kamal, Michael Hundemer, Yi Liu, Spyridoula Vasileiou, Premal Lulla, Carsten Müller-Tidow, Peter Dreger, Thomas Luft, Tim Sauer, Michael Schmitt, Judith B. Zaugg, and Caroline Pabst
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Zusammenfassung:Acute myeloid leukemia (AML) is a hematologic malignancy for which allogeneic hematopoietic cell transplantation (allo-HCT) often remains the only curative therapeutic approach. However, incapability of T cells to recognize and eliminate residual leukemia stem cells might lead to an insufficient graft-versus-leukemia (GVL) effect and relapse. Here, we performed single-cell RNA-sequencing (scRNA-seq) on bone marrow (BM) T lymphocytes and CD34+ cells of 6 patients with AML 100 days after allo-HCT to identify T-cell signatures associated with either imminent relapse (REL) or durable complete remission (CR). We observed a higher frequency of cytotoxic CD8+ effector and gamma delta (γδ) T cells in CR vs REL samples. Pseudotime and gene regulatory network analyses revealed that CR CD8+ T cells were more advanced in maturation and had a stronger cytotoxicity signature, whereas REL samples were characterized by inflammatory tumor necrosis factor/NF-κB signaling and an immunosuppressive milieu. We identified ADGRG1/GPR56 as a surface marker enriched in CR CD8+ T cells and confirmed in a CD33-directed chimeric antigen receptor T cell/AML coculture model that GPR56 becomes upregulated on T cells upon antigen encounter and elimination of AML cells. We show that GPR56 continuously increases at the protein level on CD8+ T cells after allo-HCT and confirm faster interferon gamma (IFN-γ) secretion upon re-exposure to matched, but not unmatched, recipient AML cells in the GPR56+ vs GPR56- CD8+ T-cell fraction. Together, our data provide a single-cell reference map of BM-derived T cells after allo-HCT and propose GPR56 expression dynamics as a surrogate for antigen encounter after allo-HCT.
Beschreibung:Gesehen am 15.11.2024
Beschreibung:Online Resource
ISSN:1528-0020
DOI:10.1182/blood.2023021815

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