The Remission Status of Aml Patients After Allo-Hct Is Associated With a Distinct Single-Cell Bone Marrow T-cell Signature

Authors

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
Caroline Pabst

Publication Date

3-28-2024

Journal

Blood

DOI

10.1182/blood.2023021815

PMID

38197505

PMCID

PMC10997908

PubMedCentral® Posted Date

1-11-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Humans, Bone Marrow, Leukemia, Myeloid, Acute, Hematopoietic Stem Cell Transplantation, CD8-Positive T-Lymphocytes, Recurrence

Abstract

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.