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 …