Th203 - Transcriptional Programs of Primary AML Cells Define Their Susceptibility to T Cell Killing and Correlate with Patient Survival

Rosa Bacchetta; Pauline Chen; Robert Freeborn; Andrew Gentles; Norman Lacayo; Bogdan Luca; Maria Grazia Roncarolo; Canan Sayitoglu; Benjamin Thomas; Molly Uyeda

Abstract Text: Less than 30% of patients with acute myeloid leukemia (AML) survive, and new therapeutic approaches are urgently needed. We are developing cytotoxic CD4 T cells, engineered by lentiviral gene transfer of IL10, as a therapy for AML. These CD4 T cells kill AML cells in vitro through a TCR-independent mechanism, and impair AML progression in vivo. However, some primary AML samples are resistant to killing by our cytotoxic CD4 T cells. To understand this resistance, we analyzed the single-cell transcriptome of primary AML cells and CD4 T cells before and after their in vitro interaction. This analysis uncovered transcriptional programs of AML cells that correlate with sensitivity or resistance to CD4 T cell killing. Using a large public AML RNA-seq dataset, we found the resistance-associated AML programs significantly enriched in AML patients with poor survival. Moreover, interaction with AML cells perturbed the CD4 T cell transcriptome. While killing-resistant AML cells only had a modest effect, interaction with killing-sensitive AML cells led to a strong CD4 T cell activation and AML killing. Further, we observed that killing-sensitive AML cells upregulated a gene encoding one of the key proteins required for the immune synapse formation with T cells. The knock-out of that gene from a killing-sensitive AML cell line dramatically increased its resistance to CD4 T cell killing. Altogether, we found that AML sensitivity to T cell killing depends on their ability to form an immune synapse, and AML resistance to T cell killing may contribute to poor survival of AML patients.