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

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 to primary ex vivo-isolated CD8+ T cells in vitro, and engineered CD4+ T cells in vitro and in vivo. Thus, ICAM1 on AML acts as an immune trigger, allowing T cell killing, and could affect AML patient survival in vivo. To better Understand the determinants of AML sensitivity or resistance to T cell killing, we analyzed killing-sensitive (PARCEV and PARCHW) and -resistant (PATISD and PAPZCL) primary AML samples before and after co-culture with CD4^IL10 cells (LV10_072 and LV10_2441) using single-cell RNA sequencing. Four Pediatric AML bone marrow aspirates were obtained from the Children's Oncology Group. Primary AML samples and T cells were FACs-sorted for scRNA-seq at day 0. Primary AML cells were co-cultured for 24 h with T cells at a 1:1 ratio and sorted for scRNA-seq. This was repeated twice, so that each AML sample was co-cultured with T cells from two different donors.