NK92-CD16 cells are cytotoxic to non-small cell lung cancer cell lines that have acquired resistance to tyrosine kinase inhibitors

• Published in: Cytotherapy (Oxford, England) England), 2019-06, Vol.21 (6), p.603-611
• Main Authors: PARK, HA-RAM, AHN, YONG-OON, KIM, TAE MIN, KIM, SOYEON, KIM, SEULKI, LEE, YU SOO, KIM, MISO, KEAM, BHUMSUK, KIM, DONG-WAN, HEO, DAE SEOG
• Format: Article
• Language: English
• Subjects: acquired resistance; Advanced Basic Science; Antineoplastic Agents - pharmacology; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - therapy; Cell Line, Tumor; Cell- and Tissue-Based Therapy - methods; cetuximab; Cetuximab - pharmacology; Cytotoxicity, Immunologic; Drug Resistance, Neoplasm - drug effects; Humans; Immunotherapy, Adoptive - methods; Intercellular Adhesion Molecule-1 - metabolism; intracellular adhesion molecule 1; Killer Cells, Natural - cytology; Killer Cells, Natural - physiology; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Lung Neoplasms - therapy; NK92-CD16; non-small cell lung cancer; Oncogenes; Other; Protein Kinase Inhibitors - pharmacology; Receptors, IgG - genetics
• ISSN: 1465-3249; 1477-2566
• DOI: 10.1016/j.jcyt.2019.03.312

AbstractBackgroundTreatment 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.