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

Aziez, L.; Deredec, N.; Boussaid, I.; Shasha, C. G.; Vazquez, R.; Friedrich, C.; Alik, A.; Manasse, K.; Fremont-Debaene, Z.; Barthelemy, A.; Catelain, C.; Rameau, P.; Vignon, M.; Decroocq, J.; Kosmider, O.; Selimoglu-Buet, D.; Newell, E. W.; Solary, E.; Delhommeau, F.; Herault, O.; TARTOUR, E.; Birsen, R.; Bouscary, D.; Fontenay, M.; Chapuis, N.; Simoni, Y.

doi:10.1101/2025.08.12.669682

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bioRxiv · 10.1101/2025.08.12.669682

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

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Abstract

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. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=137 SRC="FIGDIR/small/669682v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1fc9798org.highwire.dtl.DTLVardef@4491b1org.highwire.dtl.DTLVardef@1b8feadorg.highwire.dtl.DTLVardef@58515d_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Aziez, L., Deredec, N., Boussaid, I., Shasha, C. G., Vazquez, R., Friedrich, C., Alik, A., Manasse, K., Fremont-Debaene, Z., Barthelemy, A., Catelain, C., Rameau, P., Vignon, M., Decroocq, J., Kosmider, O., Selimoglu-Buet, D., Newell, E. W., Solary, E., Delhommeau, F., Herault, O., TARTOUR, E., Birsen, R., Bouscary, D., Fontenay, M., Chapuis, N., Simoni, Y.. 2025-08-15. Pro-inflammatory role of granzyme K producing bystander CD8+ T cells in acute myeloid leukemia. https://doi.org/10.1101/2025.08.12.669682

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