Effects of ADAM10 and ADAM17 Inhibitors on Natural Killer Cell Expansion and Antibody-dependent Cellular Cytotoxicity Against Breast Cancer Cells In Vitro.

Abstract

BACKGROUND/AIM:

The inhibition of a disintegrin and metalloproteinase (ADAM) has the potential to become a novel approach for natural killer (NK) cell-based cancer immunotherapy. Thus, the aim of this study was to investigate the influence of ADAM10 and ADAM17 inhibitors on expanded NK cell to enhance antibody-dependent cellular cytotoxicity (ADCC) in breast cancer cell lines.

MATERIALS AND METHODS:

NK cells were expanded in medium supplemented with an ADAM10 or ADAM17 inhibitor to prevent the shedding of soluble CD16/FcγRIII. The expression level of CD16 and production of interferon-gamma (IFN-γ) was detected by flow cytometry using specific antibodies. ADCC activity of expanded NK cells was estimated in trastuzumab treated breast cancer cell lines such as MCF-7, MDA-MB-231, SKBR3, and BT-474 cells.

RESULTS:

The ADAM17 inhibitor increased the purity of expanded NK cells to 90% after 14 days at 5 and 10 μM in vitro (p=0.043). However, the expansion rate of NK cells was decreased at 10 μM of the ADAM 17 inhibitor (p=0.043). Inhibition of ADAM10 suppressed the expansion of NK cells, although the NK purity was increased at 1 μM of the inhibitor. The expression of CD16 was significantly increased at 1 and 5 μM of the ADAM17 inhibitor (p=0.046, 0.028, respectively) during the culturing period. Inhibition of ADAM10 reduced the expression of CD16 on NK cells. The cytotoxic activity of the ADAM17 inhibitor treated NK cells against MCF-7 (p=0.039) and BT-474 (p=0.027) cells was significantly elevated. The ADCC activity of NK cells treated with 5 μM of ADAM17 inhibitor was significantly increased against SKBR-3 and BT-474 (p=0.027). Inhibition of ADAM17 increased the production of IFN-γ in expanded NK cells.

CONCLUSION:

The inhibition of ADAM17 enhanced the purity of expanded NK cells and the ADCC activity of these cells against trastuzumab treated breast cancer cell lines.

• Authors: Dang-Huan Pham, Ju-Sun Kim, Sang-Ki Kim, Dong-Jun Shin, Nguyen-Thanh-Tung Uong, Hoon Hyun, Mee Sun Yoon, Sin Jae Kang, Young Jae Ryu, Jin Seong Cho, Jung Han Yoon, Ji Shin Lee, Duck Cho, Soo-Hyeon Lee, Min Ho Park
• Journal: Anticancer research (Anticancer Res) Vol. 37 Issue 10 Pg. 5507-5513 (10 2017) ISSN: 1791-7530 [Electronic] Greece
• PMID: 28982863 (Publication Type: Journal Article)
• Copyright: Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Chemical References

• Antineoplastic Agents
• FCGR3B protein, human
• GPI-Linked Proteins
• IFNG protein, human
• Membrane Proteins
• Protease Inhibitors
• Receptors, IgG
• Interferon-gamma
• Amyloid Precursor Protein Secretases
• ADAM10 Protein
• ADAM10 protein, human
• ADAM17 Protein
• ADAM17 protein, human
• Trastuzumab

Topics

• ADAM10 Protein (antagonists & inhibitors, metabolism)
• ADAM17 Protein (antagonists & inhibitors, metabolism)
• Amyloid Precursor Protein Secretases (antagonists & inhibitors, metabolism)
• Antibody-Dependent Cell Cytotoxicity (drug effects)
• Antineoplastic Agents (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Breast Neoplasms (drug therapy, enzymology, immunology, pathology)
• Cell Proliferation (drug effects)
• Coculture Techniques
• Dose-Response Relationship, Drug
• Female
• GPI-Linked Proteins (metabolism)
• Humans
• Interferon-gamma (metabolism)
• Killer Cells, Natural (drug effects, enzymology, immunology)
• Lymphocyte Activation (drug effects)
• MCF-7 Cells
• Membrane Proteins (antagonists & inhibitors, metabolism)
• Protease Inhibitors (pharmacology)
• Receptors, IgG (metabolism)
• Time Factors
• Trastuzumab (pharmacology)
• Tumor Microenvironment