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AXL Inhibition in Macrophages Stimulates Host-versus-Leukemia Immunity and Eradicates Naïve and Treatment-Resistant Leukemia.
Tirado-Gonzalez, Irene; Descot, Arnaud; Soetopo, Devona; Nevmerzhitskaya, Aleksandra; Schäffer, Alexander; Kur, Ivan-Maximilano; Czlonka, Ewelina; Wachtel, Carolin; Tsoukala, Ioanna; Müller, Luise; Schäfer, Anna-Lena; Weitmann, Maresa; Dinse, Petra; Alberto, Emily; Buck, Michèle C; Landry, Jonathan Jm; Baying, Bianka; Slotta-Huspenina, Julia; Roesler, Jenny; Harter, Patrick N; Kubasch, Anne-Sophie; Meinel, Jörn; Elwakeel, Eiman; Strack, Elisabeth; Quang, Christine Tran; Abdel-Wahab, Omar; Schmitz, Marc; Weigert, Andreas; Schmid, Tobias; Platzbecker, Uwe; Benes, Vladimir; Ghysdael, Jacques; Bonig, Halvard; Götze, Katharina S; Rothlin, Carla V; Ghosh, Sourav; Medyouf, Hind.
Afiliación
  • Tirado-Gonzalez I; Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt am Main, Germany.
  • Descot A; Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt am Main, Germany.
  • Soetopo D; Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt am Main, Germany.
  • Nevmerzhitskaya A; Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt am Main, Germany.
  • Schäffer A; Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt am Main, Germany.
  • Kur IM; Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt am Main, Germany.
  • Czlonka E; Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt am Main, Germany.
  • Wachtel C; Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt am Main, Germany.
  • Tsoukala I; Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt am Main, Germany.
  • Müller L; Institute of Immunology, Medical Faculty Carl Gustav Carus, TU Dresden, Dresden, Germany.
  • Schäfer AL; Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt am Main, Germany.
  • Weitmann M; Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt am Main, Germany.
  • Dinse P; Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt am Main, Germany.
  • Alberto E; Department of Immunology, Yale School of Medicine, New Haven, Connecticut.
  • Buck MC; Department of Medicine III, Technical University of Munich, Munich, Germany.
  • Landry JJ; Genomics Core Facility, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
  • Baying B; Genomics Core Facility, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
  • Slotta-Huspenina J; Department of Pathology, Technical University of Munich, Munich, Germany.
  • Roesler J; Tissue biobank, Klinikum rechts der Isar and medical faculty Munich (MTBIO), Germany.
  • Harter PN; Institute of Neurology (Edinger-Institute), University Hospital Frankfurt, Goethe University, Germany.
  • Kubasch AS; Institute of Neurology (Edinger-Institute), University Hospital Frankfurt, Goethe University, Germany.
  • Meinel J; Frankfurt Cancer Institute, Goethe University, Frankfurt am Main, Germany.
  • Elwakeel E; German Cancer consortium (DKTK) & German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Strack E; Medical Clinic and Policlinic 1, Hematology and Cellular Therapy, University Hospital Leipzig, Leipzig, Germany.
  • Quang CT; Institute of Pathology, University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden, Germany.
  • Abdel-Wahab O; Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany.
  • Schmitz M; Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany.
  • Weigert A; Institut Curie, PSL Research University, CNRS UMR 3348, Orsay, France.
  • Schmid T; Université Paris Sud, Université Paris-Saclay, Orsay, France.
  • Platzbecker U; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Benes V; Institute of Immunology, Medical Faculty Carl Gustav Carus, TU Dresden, Dresden, Germany.
  • Ghysdael J; German Cancer consortium (DKTK) & German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Bonig H; German Cancer consortium (DKTK) & German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Götze KS; German Cancer consortium (DKTK) & German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Rothlin CV; Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany.
  • Ghosh S; Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany.
  • Medyouf H; German Cancer consortium (DKTK) & German Cancer Research Center (DKFZ), Heidelberg, Germany.
Cancer Discov ; 11(11): 2924-2943, 2021 11.
Article en En | MEDLINE | ID: mdl-34103328
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. SIGNIFICANCE: Alternatively primed myeloid cells predict negative outcome in leukemia. By demonstrating that leukemia cells actively evade immune control by engaging AXL receptor tyrosine kinase in macrophages and promoting their alternative priming, we identified a target which blockade, using a clinical-grade inhibitor, is vital to unleashing the therapeutic potential of myeloid-centered immunotherapy.This article is highlighted in the In This Issue feature, p. 2659.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Cancer Discov Año: 2021 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos
Texto completo
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XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Cancer Discov Año: 2021 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos