Acute leukemias are systemic malignancies associated with a dire outcome. Due to low immunogenicity, leukemias display a remarkable ability to evade immune control and are often resistant to checkpoint blockade. Here, we discover that leukemia cells actively establish a suppressive environment to prevent immune attacks by co-opting a signaling axis that skews macrophages towards a tumor promoting tissue repair phenotype, namely the GAS6/AXL axis. Using aggressive leukemia models, we demonstrate that ablation of the AXL receptor specifically in macrophages, or its ligand GAS6 in the environment, stimulates anti-leukemic immunity and elicits effective and lasting NK-and T-cell dependent immune response against naive and treatment resistant leukemia. Remarkably, AXL deficiency in macrophages also enables PD1 checkpoint blockade in PD1-refractory leukemias. Lastly, we provide proof-of-concept that a clinical grade AXL inhibitor can be used in combination with standard of care therapy to cure established leukemia, regardless on AXL expression in malignant cells.

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<p>Supplementary Methods</p>