Abstract Text: In acute myeloid leukemia (AML), a significant unmet need remains for therapeutics that selectively eradicate leukemic stem cells (LSCs) and blasts while sparing normal hematopoietic stem cells (HSCs) and healthy immune cells. LAIR-1 is an immune cell-surface expressed inhibitory receptor that has been identified as a therapeutic target in AML. LAIR-1 receptor inhibitory signaling is induced on immune cells when it binds to collagen domain-containing proteins in the extracellular matrix (ECM). However, the function of LAIR-1 on leukemic cells remains unclear. In this work, we utilized a LAIR-1 agonist monoclonal antibody (mAb) to delineate LAIR-1 signaling in leukemic cells compared to signaling in healthy cells. We show that augmentation of LAIR-1 signal transduction in AML cells by an agonist LAIR-1 mAb and ECM collagens induces cell death through mTOR and caspase-7-mediated apoptosis. Conversely, LAIR-1 signaling in healthy cells does not induce cell death, and instead regulates TNFα, IL-6, and IL-17 cytokine production in response to LPS and interferon danger stimuli. Importantly, multiple in vivo and ex vivo models demonstrate that targeting LAIR-1 with an agonist mAb kills LSCs and blasts without adversely affecting HSCs or healthy leukocytes. This novel mechanism of LAIR-1 function provides a unique therapeutic opportunity in myeloid leukemias via agonism of the LAIR-1 receptor.
