Coordinated immune networks in leukemia bone marrow microenvironments distinguish response to cellular therapy

Understanding how intratumoral immune populations coordinate antitumor responses after therapy can guide treatment prioritization. We systematically analyzed an established immunotherapy, donor lymphocyte infusion (DLI), by assessing 348,905 single-cell transcriptomes from 74 longitudinal bone marrow samples of 25 patients with relapsed leukemia; a subset was evaluated by both protein- and transcriptome-based spatial analysis. In acute myeloid leukemia (AML) DLI responders, we identified clonally expanded ZNF683 + CD8 + cytotoxic T lymphocytes with in vitro specificity for patient-matched AML. These cells originated primarily from the DLI product and appeared to coordinate antitumor immune responses through interaction with diverse immune cell types within the marrow microenvironment. Nonresponders lacked this cross-talk and had cytotoxic T lymphocytes with elevated TIGIT expression. Our study identifies recipient bone marrow microenvironment differences as a determinant of an effective antileukemia response and opens opportunities to modulate cellular therapy.