Human type-1 innate lymphoid cells control leukemia stem cell differentiation and limit acute myeloid leukemia development

Innate lymphoid cells (ILCs) are crucial for cancer immunosurveillance. While mouse type 1 ILCs (ILC1s) control acute myeloid leukemia (AML) by targeting leukemia stem cells (LSCs), the role of human ILC1s in AML remains largely undefined. Here, we find that ILC1s in AML patients are impaired, with reduced total ILC1 numbers and diminished function. In contrast, healthy donor (HD) ILC1s-derived TNFα inhibits the leukemic transition from CD34⁺CD38⁺ to CD34^-CD38⁺ cells and blocks the differentiation of LSCs (CD34⁺CD38^-) into immunosuppressive, macrophage-like leukemia-supporting cells. HD ILC1-derived IFNγ partially suppresses the differentiation of CD34^-CD38⁺ to CD34^-CD38^- cells. These combined effects limit human leukemogenesis in vivo. We also identify a human ILC1 subset as Lin^-CD127⁺CD161^-CRTH2^-CD117^- (CD161^- ILC1s) that can be generated from umbilical cord blood CD34⁺ hematopoietic stem cells. This method could provide a reliable source of ILC1s for potential adoptive transfer therapies in AML, offering a therapeutic approach to prolong disease-free survival in AML.