AML/T cell interactomics uncover correlates of patient outcomes and the key role of ICAM1 in T cell killing of AML

Abstract T 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 cells in vitro. Killing-sensitive AML potently activated T cells before being killed, and upregulated ICAM1 , a key component of the immune synapse with T cells. Without ICAM1, killing-sensitive AML became resistant to killing by primary ex vivo-isolated CD8 + T cells in vitro, and engineered CD4 + T cells in vitro and in vivo. While AML heterogeneity implies that multiple factors may determine their sensitivity to T cell killing, these data show that ICAM1 acts as an immune trigger, allowing T cell killing, and could play a role in AML patient survival in vivo.