Genetic and clinical evidence supports HLA-DR+ CD8+ T cells as a favorable immune biomarker in acute myeloid leukemia.

Immune dysregulation is central to acute myeloid leukemia (AML), but the contribution of specific immune subsets remains uncertain. We combined Mendelian randomization (MR), clinical flow cytometry, and transcriptomic profiling to investigate HLA-DR+ CD8+ T cells in AML. Two-sample MR using 731 immunophenotypes and AML data from UK Biobank and FinnGen identified four HLA-DR-related T-cell traits associated with lower AML susceptibility. In 85 non-APL patients, HLA-DR+ CD8+ T-cell proportions increased after complete remission, while among 46 newly diagnosed patients, a lower baseline HLA-DR+ CD8+ T-cell proportion was associated with poorer overall survival after adjustment for age and ELN risk category (HR 3.32, 95% CI 1.09-10.16, P = 0.035). A nomogram incorporating clinical and immune variables stratified patient risk. Transcriptomic analysis linked lower HLA-DR+ CD8+ T-cell levels to ribosomal and extracellular matrix pathways. These findings support HLA-DR+ CD8+ T cells as a favorable immune biomarker and clinically relevant immune correlate in AML.