Axl inhibition in macrophages stimulates host-versus-leukemia immunity and eradicates naïve and treatment-resistant leukemia

Irene Tirado-Gonzalez, Arnaud Descot, Devona Soetopo, Aleksandra Nevmerzhitskaya, Alexander Schäffer, Ivan Maximilano Kur, Ewelina Czlonka, Carolin Wachtel, Ioanna Tsoukala, Luise Müller, Anna Lena Schäfer, Maresa Weitmann, Petra Dinse, Emily Alberto, Michèle C. Buck, Jonathan Jm Landry, Bianka Baying, Julia Slotta-Huspenina, Jenny Roesler, Patrick N. HarterAnne Sophie Kubasch, Jörn Meinel, Eiman Elwakeel, Elisabeth Strack, Christine Tran Quang, Omar Abdel-Wahab, Marc Schmitz, Andreas Weigert, Tobias Schmid, Uwe Platzbecker, Vladimir Benes, Jacques Ghysdael, Halvard Bonig, Katharina S. Götze, Carla V. Rothlin, Sourav Ghosh, Hind Medyouf

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

Acute leukemias are systemic malignancies associated with a dire outcome. Because of 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 toward 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 antileukemic immunity and elicits effective and lasting natural killer cell– and T cell–dependent immune response against naïve and treatment-resistant leukemia. Remarkably, AXL deficiency in macrophages also enables PD-1 checkpoint blockade in PD-1–refractory leukemias. Finally, 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 of AXL expression in malignant cells.

Original languageEnglish
Pages (from-to)2924-2943
Number of pages20
JournalCancer Discovery
Volume11
Issue number11
DOIs
StatePublished - Nov 2021

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