Single-cell dissection of self-derived versus donor-derived T cell exhaustion niches in patients with acute myeloid leukemia

Relapse remains the main cause of death in acute myeloid leukemia (AML), and T cell exhaustion is related to relapse in both non-allografting and allografting settings. However, differences in exhausted T cells (T ex ) across different disease contexts remain incompletely understood. We performed single-cell RNA and T cell receptor (TCR) sequencing to systematically characterize T ex in AML. Both self-derived T ex in non-transplantation and donor-derived T ex in post-transplant settings express similar surface markers, but NFATC1/NFATC3 with downstream TOX and EOMES are enriched in self-derived T ex , while NFATC2 with downstream NR4A2 predominates in donor-derived T ex . Both self-derived and donor-derived bone marrow environments are enriched with immunosuppressive monocytes, dendritic cells, and regulatory T cells. Cell-cell interaction analysis reveals strong direct and indirect interactions between T ex and AML cells, primarily mediated by galectin-9, MIF, and TGF-β1. These findings highlight differences and commonalities between self-derived and donor-derived T ex and identify potential therapeutic targets for reversing T ex in AML.