NK92-CD16 cells are cytotoxic to non-small cell lung cancer cell lines that have acquired resistance to tyrosine kinase inhibitors |
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| Institution: | 1. Seoul National University Cancer Research Institute, Seoul, Republic of Korea;2. Department of Internal Medicine;3. Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea;4. Medical Research Center and Department of Laboratory Medicine, Seoul National University College of Medicine;1. Drug Discovery Antibody Platform Unit, RIKEN Center for Integrative Medical Science (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan;2. Drug Discovery Structural Biology Platform Unit, RIKEN Center for Biosystems Dynamics Research (BDR), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan;3. RIKEN Systems and Structural Biology Center (SSBC), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan;4. Laboratory for Human Disease Models, RIKEN Center for Integrative Medical Science (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, 230-0045, Japan;5. Division of Hematological Malignancy, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan;1. Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA;2. Vasculox, Inc., St. Louis, MO, USA;3. Department of Cardiovascular Medicine, Stanford University, Palo Alto, CA, USA;4. Departments of Biochemistry and Molecular Biophysics, Cell Biology, and Physiology, Washington University School of Medicine, St. Louis, MO, USA;5. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA;1. Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt, Germany;2. Division for Stem Cell Transplantation and Immunology, Hospital for Children and Adolescents, Goethe University Frankfurt, Frankfurt, Germany;3. LOEWE Center for Cell and Gene Therapy, Goethe University Frankfurt, Frankfurt, Germany;4. Department of Medicine, Hematology and Oncology, Goethe University Frankfurt, Frankfurt, Germany;5. Department of Haematology, Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, United Kingdom;6. NantKwest, Inc., Culver City, California, USA;7. Institute for Transfusion Medicine, German Red Cross Blood Donation Service North-East, Dresden and Transfusion Medicine, Medical Faculty Carl Gustav Carus, TU Dresden, Germany;8. German Cancer Consortium (DKTK), partner site Frankfurt/Mainz, Germany |
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| Abstract: | BackgroundTreatment with tyrosine kinase inhibitors (TKIs) has improved the outcomes for patients with non-small cell lung cancer (NSCLC) harboring targetable driver mutations. However, acquired resistance to TKIs invariably develops within approximately 1 year of treatment by various mechanisms, including gatekeeper mutations, alternative pathway activation and histological transformations. Because immunotherapy is an option for patients with drug-resistant cancers, we generated several TKI-resistant NSCLC cell lines in vitro, and then evaluated the cytotoxicity of NK92-CD16 cells to these resistant cells.Materials and MethodsTKI-resistant NSCLC cells (H3122CR1, H3122LR1, H3122CR1LR1, PC-9GR, PC-9ER, EBC-CR1 and EBC-CR2) were established from NCI-H3122 (EML4-ALK fusion), PC-9 (EGFR exon19 deletion) and EBC-1 (MET amplification) after continuous exposure to crizotinib, ceritinib, gefitinib, erlotinib and capmatinib. Expression of ligands for natural killer (NK) cell receptors and total EGFR were analyzed using flow cytometry. NK cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC) using anti-EGFR monoclonal antibody (mAb) cetuximab were measured using NK92-CD16 as effectors and detected using the 51Chromium-release assay.ResultsWe found that NK92-CD16 cells preferentially killed TKI-resistant NSCLC cells when compared with their parental NSCLC cells. Mechanistically, intracellular adhesion molecule 1 (ICAM-1) was up-regulated in the TKI-resistant NSCLC cells and patients’ tumors, and the ICAM-1 up-regulated cancer cells lines were less susceptible to NK cytotoxicity by blocking ICAM-1. Moreover, NK92-CD16 cell-induced cytotoxicity toward TKI-resistant NSCLC cells was enhanced in the presence of cetuximab, an EGFR-targeting mAb.ConclusionThese data suggest that combinational treatment with NK cell–based immunotherapy and cetuximab may be promising for patients with TKI-resistant NSCLC. |
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