Sandén and Landberg et al. demonstrated that lymphoid surface protein SLAMF6 is overexpressed in 60% of primitive AML cells across all subtypes. High SLAMF6 expression correlated with enrichment of naive T cells and decreased memory T cells. Homotypic SLAMF6–SLAMF6 interactions between AML cells and T cells suppressed T cell activation. SLAMF6 KO sensitized AML cells to T cell killing, without affecting leukemic cell proliferation. An antibody blocking SLAMF6–SLAMF6 interactions restored T cell cytotoxicity in vitro, and reduced leukemia burden in bone marrow and spleens in a humanized HNT-34 AML mouse model.
Contributed by Shishir Pant
ABSTRACT: 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.
Author Info: (1) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. carl.sanden@med.lu.se. (2) Division of Clinical Genetics, Department of Laborat
Author Info: (1) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. carl.sanden@med.lu.se. (2) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. Department of Hematology, Oncology and Radiation Physics, Skne University Hospital, Lund, Sweden. (3) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. (4) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. (5) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. (6) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. (7) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. (8) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. (9) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. (10) Department of Hematology, Oncology and Radiation Physics, Skne University Hospital, Lund, Sweden. (11) Department of Hematology, Oncology and Radiation Physics, Skne University Hospital, Lund, Sweden. (12) Department of Immunotechnology, Lund University, Lund, Sweden. SciLifeLab Drug Discovery and Development Platform, Lund University, Lund, Sweden. (13) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. (14) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. Department of Clinical Genetics, Pathology, and Molecular Diagnostics, Skne University Hospital, Region Skne, Lund, Sweden. (15) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. (16) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. Department of Clinical Genetics, Pathology, and Molecular Diagnostics, Skne University Hospital, Region Skne, Lund, Sweden. (17) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. thoas.fioretos@med.lu.se. Department of Clinical Genetics, Pathology, and Molecular Diagnostics, Skne University Hospital, Region Skne, Lund, Sweden. thoas.fioretos@med.lu.se.
