Browse

Cytotoxicity of NK92-CD16 cells on NSCLC cell line resistant to TKI : 티로신 키나아제 억제제에 대한 획득내성이 생긴 비소세포폐암에서 NK92-CD16 세포의 항암 효과 연구

Cited 0 time in Web of Science Cited 0 time in Scopus
Authors
박하람
Advisor
허대석
Major
의과대학 협동과정 종양생물학전공
Issue Date
2017-08
Publisher
서울대학교 대학원
Keywords
NK-92Non-small cell lung canceracquired resistance
Description
학위논문 (석사)-- 서울대학교 대학원 의과대학 협동과정 종양생물학전공, 2017. 8. 허대석.
Abstract
Purpose: The use of tyrosine kinase inhibitor (TKIs) improved outcome of non-small cell lung cancer (NSCLC) patients harboring targetable driver mutation. However, the most patients eventually showed disease progression due to the acquired resistance to TKIs by various mechanisms including gatekeeper mutation and alternative pathway activation. As immunotherapy can be considered for these patients to override drug resistance, I investigated the efficacy of NK92-CD16 cells (CD16-transduced NK-92 cell line) to TKI-resistant NSCLC cells.
Methods: TKI-resistant NSCLC cells (H3122CR1, H3122LR1, H3122CR1LR1, EBC-CR1, EBC-CR2, PC-9GR and PC-9ER) were established from NCI-H3122 (EML4-ALK fusion), EBC-1 (MET amplification), and PC-9 (EGFR exon 19 deletion) after continuous exposure to crizotinib, ceritinib, capmatinib, gefitinib, and erlotinib. NK cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC) using anti-EGFR monoclonal antibody (mAb) cetuximab were measured using off-the-shelf NK92-CD16 as effectors and detected by the 51Chromium-release assay. Expression of the ligands for NK cell receptors and total EGFR were analyzed by flow cytometry.
Results: Most of TKI-resistant NSCLC cell lines were more susceptible to NK92-CD16 cell compared with their parental cell lines. The expression of ICAM-1, which is a ligand for LFA-1 in NK cells, is higher in TKI-resistant NSCLC cells than in parental cells and is expected to be correlated with NK92-CD16 cytotoxicity. When ICAM1-CD11a interaction was blocked during a cytotoxic assay, the cytotoxicity was decreased. Cetuximab-mediated ADCC was higher in resistant cells due to the increased expression level of total EGFR in resistant cells.
Conclusions: TKI-resistant NSCLC cells are more sensitive to NK92-CD16 cell-mediated cytotoxicity that is partially dependent on up-regulation of ICAM-1 via an immunological synapse. In addition, cetuximab, an EGFR-targeting mAb, significantly increases NK cell cytotoxicity in TKI-resistant NSCLC cells. Taken together, NK-cell based immunotherapy with cetuximab might be feasible to treat NSCLC patients with acquired resistance to TKIs.
Language
English
URI
https://hdl.handle.net/10371/138005
Files in This Item:
Appears in Collections:
College of Medicine/School of Medicine (의과대학/대학원)Program in Cancer Biology (협동과정-종양생물학전공)Theses (Master's Degree_협동과정-종양생물학전공)
  • mendeley

Items in S-Space are protected by copyright, with all rights reserved, unless otherwise indicated.

Browse