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

抗体依赖性细胞介导的细胞毒性 癌症研究 CD16 细胞毒性 细胞毒性T细胞 酪氨酸激酶 吉非替尼 肺癌 化学 单克隆抗体 表皮生长因子受体 免疫学 生物 癌症 医学 抗体 内科学 体外 CD8型 抗原 CD3型 受体 生物化学
作者
Ha A.R.A.M. Park,Yong Oon Ahn,Tae Min Kim,Soyeon Kim,Seulki Kim,Yu Soo Lee,M. I.S.O. Kim,Bhumsuk Keam,Dong O.N.G.W.A.N. Kim,Dae Seog Heo
出处
期刊:Cytotherapy [Elsevier]
卷期号:21 (6): 603-611 被引量:16
标识
DOI:10.1016/j.jcyt.2019.03.312
摘要

Background Treatment 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 Methods TKI-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. Results We 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. Conclusion These 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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