Abstract
ABSTRACTT cells are important for the control of acute myeloid leukemia (AML), a common and often deadly malignancy. We observed that some AML patient samples are resistant to killing by human engineered cytotoxic CD4+T cells. Single-cell RNA-seq of primary AML samples and CD4+T cells before and after their interaction uncovered transcriptional programs that correlate with AML sensitivity or resistance to CD4+T cell killing. Resistance-associated AML programs were enriched in AML patients with poor survival, and killing-resistant AML cells did not engage T cellsin vitro. Killing-sensitive AML potently activated T cells before being killed, and upregulatedICAM1, a key component of the immune synapse with T cells. Without ICAM1, killing-sensitive AML became resistant to killing to primaryex vivo-isolated CD8+T cellsin vitro, and engineered CD4+T cellsin vitroandin vivo. Thus, ICAM1 on AML acts as an immune trigger, allowing T cell killing, and could affect AML patient survivalin vivo.SIGNIFICANCEAML is a common leukemia with sub-optimal outcomes. We show that AML transcriptional programs correlate with susceptibility to T cell killing. Killing resistance-associated AML programs are enriched in patients with poor survival. Killing-sensitive, but not resistant AML activate T cells and upregulateICAM1that binds to LFA-1 on T cells, allowing immune synapse formation which is critical for AML elimination.GRAPHICAL ABSTRACT
Publisher
Cold Spring Harbor Laboratory