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<p>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 <i>SLAMF6</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月3日

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  • Carl Sandén,
  • Niklas Landberg,
  • Pablo Peña-Martínez,
  • Hanna Thorsson,
  • Shruti Daga,
  • Noelia Puente-Moncada,
  • Maria Rodriguez-Zabala,
  • Sofia von Palffy,
  • Marianne Rissler,
  • Vladimir Lazarevic,
  • Gunnar Juliusson,
  • Mats Ohlin,
  • Axel Hyrenius-Wittsten,
  • Christina Orsmark-Pietras,
  • Henrik Lilljebjörn,
  • Helena Ågerstam,
  • Thoas Fioretos

摘要

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.