CD8⁺ T-cell differentiation and dysfunction inform treatment response in acute myeloid leukemia

• Bone marrow CD8⁺ T-cell differentiation states play a crucial role in patients with AML response to therapy.

• Single-cell RNA sequencing analysis reveals developmental dichotomic programs and clonal expansion in relation to therapy response in AML.

The interplay between T-cell states of differentiation, dysfunction, and treatment response in acute myeloid leukemia (AML) remains unclear. Here, we leveraged a multimodal approach encompassing high-dimensional flow cytometry and single-cell transcriptomics and found that early memory CD8⁺ T cells are associated with therapy response and exhibit a bifurcation into 2 distinct terminal end states. One state is enriched for markers of activation, whereas the other expresses natural killer (NK)-like and senescence markers. The skewed clonal differentiation trajectory toward CD8⁺ senescence was also a hallmark indicative of therapy resistance. We validated these findings by generating an AML CD8⁺ single-cell atlas integrating our data and other independent data sets. Finally, our analysis revealed that an imbalance between CD8⁺ early memory and senescent-like cells is linked to AML treatment refractoriness and poor survival. Our study provides crucial insights into the dynamics of CD8⁺ T-cell differentiation and advances our understanding of CD8⁺ T-cell dysfunction in AML.