TY - JOUR T1 - AXL targeting overcomes human lung cancer cell resistance to NK and CTL-mediated cytotoxicity JF - Cancer Immunology Research JO - Cancer Immunol Res DO - 10.1158/2326-6066.CIR-18-0903 SP - canimm.0903.2019 AU - Terry, Stéphane AU - Abdou, Abderemane AU - Engelsen, Agnete S.T. AU - Buart, Stéphanie AU - Dessen, Philippe AU - Corgnac, Stephanie AU - Collares, Davi AU - Meurice, Guillaume AU - Gausdal, Gro AU - Baud, Veronique AU - Saintigny, Pierre AU - Lorens, James B. AU - Thiery, Jean Paul AU - Mami-Chouaib, Fathia AU - Chouaib, Salem Y1 - 2019/01/01 UR - http://cancerimmunolres.aacrjournals.org/content/early/2019/09/05/2326-6066.CIR-18-0903.abstract N2 - 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 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 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. ER -