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AXL Targeting Overcomes Human Lung Cancer Cell Resistance to NK- and CTL-Mediated Cytotoxicity

Stéphane Terry, Abderemane Abdou, Agnete S.T. Engelsen, Stéphanie Buart, Philippe Dessen, Stéphanie Corgnac, Davi Collares, Guillaume Meurice, Gro Gausdal, Véronique Baud, Pierre Saintigny, James B. Lorens, Jean-Paul Thiery, Fathia Mami-Chouaib and Salem Chouaib
Stéphane Terry
INSERM UMR1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, Equipe Labellisée par la Ligue Contre le Cancer, EPHE, Faculté de Médecine, Université Paris-Sud, Université Paris-Saclay, Villejuif, France.
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Abderemane Abdou
INSERM UMR1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, Equipe Labellisée par la Ligue Contre le Cancer, EPHE, Faculté de Médecine, Université Paris-Sud, Université Paris-Saclay, Villejuif, France.
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Agnete S.T. Engelsen
INSERM UMR1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, Equipe Labellisée par la Ligue Contre le Cancer, EPHE, Faculté de Médecine, Université Paris-Sud, Université Paris-Saclay, Villejuif, France.Department of Biomedicine, Centre for Cancer Biomarkers, Norwegian Centre of Excellence, University of Bergen, Bergen, Norway.
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  • ORCID record for Agnete S.T. Engelsen
Stéphanie Buart
INSERM UMR1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, Equipe Labellisée par la Ligue Contre le Cancer, EPHE, Faculté de Médecine, Université Paris-Sud, Université Paris-Saclay, Villejuif, France.
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Philippe Dessen
Plateforme de Bioinformatique, UMS AMMICA, Gustave Roussy, Villejuif, France.
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Stéphanie Corgnac
INSERM UMR1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, Equipe Labellisée par la Ligue Contre le Cancer, EPHE, Faculté de Médecine, Université Paris-Sud, Université Paris-Saclay, Villejuif, France.
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Davi Collares
NF-κB, Differentiation and Cancer, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
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Guillaume Meurice
Plateforme de Bioinformatique, UMS AMMICA, Gustave Roussy, Villejuif, France.
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Gro Gausdal
BerGenBio ASA, Bergen, Norway.
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Véronique Baud
NF-κB, Differentiation and Cancer, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
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  • ORCID record for Véronique Baud
Pierre Saintigny
Univ Lyon, Université Claude Bernard Lyon 1, INSERM, CNRS, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France.Department of Medical Oncology, Centre Léon Bérard, Lyon, France.
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James B. Lorens
Department of Biomedicine, Centre for Cancer Biomarkers, Norwegian Centre of Excellence, University of Bergen, Bergen, Norway.
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Jean-Paul Thiery
INSERM UMR1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, Equipe Labellisée par la Ligue Contre le Cancer, EPHE, Faculté de Médecine, Université Paris-Sud, Université Paris-Saclay, Villejuif, France.Department of Biomedicine, Centre for Cancer Biomarkers, Norwegian Centre of Excellence, University of Bergen, Bergen, Norway.Department of Biochemistry, National University of Singapore, Singapore, Singapore.Institute of Molecular and Cell Biology, A-STAR, Singapore, Singapore.
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Fathia Mami-Chouaib
INSERM UMR1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, Equipe Labellisée par la Ligue Contre le Cancer, EPHE, Faculté de Médecine, Université Paris-Sud, Université Paris-Saclay, Villejuif, France.
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Salem Chouaib
INSERM UMR1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, Equipe Labellisée par la Ligue Contre le Cancer, EPHE, Faculté de Médecine, Université Paris-Sud, Université Paris-Saclay, Villejuif, France.Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates.
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  • For correspondence: salem.chouaib@gustaveroussy.fr
DOI: 10.1158/2326-6066.CIR-18-0903 Published November 2019
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Abstract

Immune resistance may arise from both genetic instability and tumor heterogeneity. Microenvironmental stresses such as hypoxia and various resistance mechanisms promote carcinoma cell plasticity. AXL, a member of the TAM (Tyro3, Axl, and Mer) receptor tyrosine kinase family, is widely expressed in human cancers and increasingly recognized for its role in cell plasticity and drug resistance. To investigate mechanisms of immune resistance, we studied multiple human lung cancer clones derived from a model of hypoxia-induced tumor plasticity that exhibited mesenchymal or epithelial features. We demonstrate that AXL expression is increased in mesenchymal lung cancer clones. Expression of AXL in the cells correlated with increased cancer cell–intrinsic resistance to both natural killer (NK)– and cytotoxic T lymphocyte (CTL)–mediated killing. A small-molecule targeting AXL sensitized mesenchymal lung cancer cells to cytotoxic lymphocyte–mediated killing. Mechanistically, we showed that attenuation of AXL-dependent immune resistance involved a molecular network comprising NF-κB activation, increased ICAM1 expression, and upregulation of ULBP1 expression coupled with MAPK inhibition. Higher ICAM1 and ULBP1 tumor expression correlated with improved patient survival in two non–small cell lung cancer (NSCLC) cohorts. These results reveal an AXL-mediated immune-escape regulatory pathway, suggest AXL as a candidate biomarker for tumor resistance to NK and CTL immunity, and support AXL targeting to optimize immune response in NSCLC.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

  • Cancer Immunol Res 2019;7:1789–802

  • Received January 2, 2019.
  • Revision received May 29, 2019.
  • Accepted August 30, 2019.
  • Published first September 5, 2019.
  • ©2019 American Association for Cancer Research.
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Cancer Immunology Research: 7 (11)
November 2019
Volume 7, Issue 11
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AXL Targeting Overcomes Human Lung Cancer Cell Resistance to NK- and CTL-Mediated Cytotoxicity
Stéphane Terry, Abderemane Abdou, Agnete S.T. Engelsen, Stéphanie Buart, Philippe Dessen, Stéphanie Corgnac, Davi Collares, Guillaume Meurice, Gro Gausdal, Véronique Baud, Pierre Saintigny, James B. Lorens, Jean-Paul Thiery, Fathia Mami-Chouaib and Salem Chouaib
Cancer Immunol Res November 1 2019 (7) (11) 1789-1802; DOI: 10.1158/2326-6066.CIR-18-0903

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AXL Targeting Overcomes Human Lung Cancer Cell Resistance to NK- and CTL-Mediated Cytotoxicity
Stéphane Terry, Abderemane Abdou, Agnete S.T. Engelsen, Stéphanie Buart, Philippe Dessen, Stéphanie Corgnac, Davi Collares, Guillaume Meurice, Gro Gausdal, Véronique Baud, Pierre Saintigny, James B. Lorens, Jean-Paul Thiery, Fathia Mami-Chouaib and Salem Chouaib
Cancer Immunol Res November 1 2019 (7) (11) 1789-1802; DOI: 10.1158/2326-6066.CIR-18-0903
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