Pro-inflammatory role of granzyme K producing bystander CD8 ⁺ T cells in acute myeloid leukemia

Acute myeloid leukemia (AML) is a heterogeneous group of blood malignancies with a 5-year survival rate below 30%, highlighting the urgent need for more effective therapeutic strategies. T cell-based immunotherapies have demonstrated remarkable success in solid tumors, yet the role of CD8 ⁺ T cells in AML remains unclear. In this study, we analyzed the composition, antigenic specificity, and function of CD8 ⁺ T cells in paired blood and bone marrow samples from AML patients. While we did not identify exhausted CD8 ⁺ T cells as seen in solid tumors, we observed a distinct population of functional CD69 ⁺ CD8 ⁺ T cells specifically enriched in the bone marrow. These cells primarily recognized non-tumor antigens, including epitopes derived from Epstein–Barr virus (EBV) and cytomegalovirus (CMV). Notably, this bystander CD8 ⁺ T cell population showed high expression of Granzyme K, a cytokine found in the bone marrow of AML patients. Granzyme K did not induce leukemic cell death but instead promoted the secretion of IL-8, a pro-inflammatory cytokine known to play a detrimental role in AML pathology. Rather than mounting an anti-tumor response, these CD8 ⁺ T cells contribute to a pro-inflammatory environment that may exacerbate AML progression and severity. These findings provide a rationale for exploring therapeutic strategies aimed at inhibiting pro-inflammatory CD8 ⁺ T cells and targeting Granzyme K activity in association with actual therapies.