Differences in the bone marrow microenvironment may determine why some relapsed acute myeloid leukemia (AML) patients respond better to donor lymphocyte infusion (DLI) after hematopoietic stem cell transplantation (HSCT), according to a study published in Science Immunology.
The study was led by first author Katie Maurer, MD, PhD, a physician-scientist at the Dana-Farber Cancer Institute.
DLI is successful in only about 15%-20% of patients with AML. Further, exactly how the cells in the DLI product help move leukemia into remission are not known, making it difficult for clinicians to improve the treatment.
“Relapse of AML after stem cell transplant is a major challenge,” Dr. Maurer said in a press release published by Dana-Farber. “There are few effective therapies, and patient outcomes after relapse are poor.”
Dr. Maurer and colleagues used single cell sequencing techniques to analyze the bone marrow of 25 AML patients with AML who had relapsed and been treated with HSCT and DLI (the analysis included patients who responded and did not respond to treatment). The 25 patients yielded 74 longitudinal bone marrow samples generating 348,905 single-cell transcriptomes.
The results showed that patients who responded to DLI therapy had notably different cellular populations in their bone marrow compared to patients who did not respond. Specifically, responders demonstrated coordinated dynamic expansion of T and natural killer (NK) cells with predicted direct interactions with leukemia cells, whereas nonresponders revealed relative “neglect” from infiltrating immune cell populations.
“This concept is reminiscent of the ‘hot’ and ‘cold’ tumor paradigm,” the authors wrote, referring to similar differences observed in the responses of AML patients treated with immune checkpoint blockade.
The team also identified a single immune cell type that appears to mediate whether the responders’ donor cells include active immune cells that can attack leukemia cells that remain in the patient after the transplant. The cell type, CD8-positive cytotoxic T lymphocytes (CTLs) that express a transcription factor called ZNF683/Hobit at high levels, appear to coordinate with other immune cells to expand and attack leukemia cells. In patients who did not respond, these T cells had lower levels of expression of ZNF683/Hobit and higher levels of markers that inhibit their activity.
The researchers also devised an in vitro co-culture assay to verify that the CD8-positive CTLs they identified exhibited functional antileukemic activity after encounter with leukemia cells from the same patient.
“The goal of our research is to identify the ways in which some patients respond, in the hopes that uncovering these mechanisms can help us create improved therapies that are more effective for a greater number of patients,” Dr Maurer said. “In this project, we identified a specific subset of activated T cells that have anti-leukemic activity. This discovery paves the way for creation of T cell therapies with improved efficacy in treating AML.”
Reference
Maurer K, Park CY, Mani S, et al. Coordinated immune networks in leukemia bone marrow microenvironments distinguish response to cellular therapy. Sci Immunol. 2025;10(103):eadr0782. doi:10.1126/sciimmunol.adr0782
