Aberrant expression of SLAMF6 constitutes a targetable immune escape mechanism in acute myeloid leukemia.

Sandén C, Landberg N, Peña-Martínez P, Thorsson H, Daga S, Puente-Moncada N, Rodriguez-Zabala M, von Palffy S, Rissler M, Lazarevic V, Juliusson G, Ohlin M, Hyrenius-Wittsten A, Orsmark-Pietras C, Lilljebjörn H, Ågerstam H, Fioretos T

Nat Cancer - (-) - [2025-10-03; online 2025-10-03]

Immunotherapy has shown limited success in acute myeloid leukemia (AML), indicating an incomplete understanding of the underlying immunoregulatory mechanisms. Here we identify an immune evasion mechanism present in 60% of AML cases, wherein primitive AML cells aberrantly express the lymphoid surface protein SLAMF6 (signaling lymphocyte activation molecule family member 6). Knockout of SLAMF6 in AML cells enables T cell activation and highly efficient killing of leukemia cells in coculture systems, demonstrating that SLAMF6 protects AML cells from recognition and elimination by the immune system in a mode analogous to the programmed cell death protein-ligand (PDL1/PD1) axis. Targeting SLAMF6 with an antibody against the SLAMF6 dimerization site inhibits the SLAMF6-SLAMF6 interaction and induces T cell activation and killing of AML cells both in vitro and in humanized in vivo models. In conclusion, we show that aberrant expression of SLAMF6 is a common and targetable immune escape mechanism that could pave the way for immunotherapy in AML.

Clinical Genomics Lund [Service]

Drug Discovery and Development [Collaborative]

PubMed 41044242

DOI 10.1038/s43018-025-01054-6

Crossref 10.1038/s43018-025-01054-6

pii: 10.1038/s43018-025-01054-6