In the Right Place and the Right State: Spatial Crosstalk and Immune State Dictate Leukemia Response to Immunotherapy

Abstract Donor Lymphocyte Infusion (DLI) is a crucial therapeutic strategy for relapsed myeloid malignancies post-allogeneic hematopoietic cell transplantation (allo-HCT), leveraging the graft-versus-leukemia (GvL) effect to restore immune control. While highly effective in chronic myeloid leukemia (CML), its efficacy in acute myeloid leukemia (AML) remains limited, with underlying mechanisms not fully understood. Recent research by Maurer and colleagues utilized cutting-edge technologies to dissect immune-leukemia interactions within the bone marrow niche, identifying a cytotoxic CD8+ T cell population as a key mediator of the anti-leukemic response. The study highlights a dynamic expansion of T and NK cells in responders, whereas non-responders display an immune suppressive bone marrow niche. TCR tracking revealed that the primary effectors of GvL in AML originate from the DLI infusion, yet their activation depends on a permissive bone marrow microenvironment. These insights emphasize that leukemia progression and immune response are shaped not only by malignant cells but also by broader niche dynamics. Further investigation is needed to define the different mechanisms that drives response or resistance to cellular therapies, but also to dissect the antigenic specificity of GvL-mediating T cells and define biomarkers predicting response to DLI.