Effect of interleukins (IL-2, IL-15, IL-18) on receptors activation and cytotoxic activity of natural killer cells in breast cancer cell

Abstract

Introduction: Breast cancer is one of the leading cause of cancer deaths in women. Metastasis in BC is caused by immuno- surveillance deficiency, such NK cell maturation, low NK activity and decreasing cytotoxicity. This study was performed to improve activating receptors and cytotoxicity of NK cells using interleukins (ILs).
 Methods: Human recombinant IL-2, -15, and -18 were used to induce NK cells. We measured the activating and inhibiting receptors, proliferation activity of NK cells, and the cytotoxicity of NK cells on BC cells (MCF7). The effects of ILs were tested on the NK cell receptors CD314, CD158a and CD107a with flowcytometry, proliferation at various incubation times with 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxy methoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and concen- trations of TNF-α and IFN-γ by NK cells with ELISA.
 Results: ILs increased NK cell receptor levels (CD314, CD158a, and CD107a) at 24 hours of incubation. ILs increased NK cell viability, which increased with longer incubation. Moreover, ILs-induced NK cells inhibited proliferation in MCF7 cells, as well as increased TNF-α, IFN-γ, PRF1 and GzmB secretion.
 Conclusion: IL-2, IL-15, and IL-18 improved activating receptors and proliferation of NK cells. IL-induced NK cells in- creased TNF-α, IFN-γ, PRF1 and GzmB secretion and cytotoxic activity on BC cells. High NK cell numbers increased BC cell growth inhibition.
 Keywords: Activator; breast cancer; interleukins; natural killer; receptor.

RETRACTED: CAR-NK Cell: A New Paradigm in Tumor Immunotherapy

“…Triggered NK cells can kill cancerous cells by direct cell cytotoxicity and/or generation of pro-inflammatory cytokines. In addition to the releases of perforin and granzymes for tumor cell elimination, NK cells exert antibody-dependent cellular cytotoxicity (ADCC) by the membrane receptor CD16 or apoptotic axis intermediated by Fas ligand (FasL) or TNF-related apoptosis-inducing ligand (TRAIL) ( Figure 1 ) ( 12 , 13 ). Furthermore, modulation of anti-tumor immune responses by NK cells leads to secretion of cytokines and chemokines including interferon-γ (IFN-γ) and granulocyte-macrophage colony-stimulating factor (GM-CSF) ( 14 ).…”

Apoptotic Potential of Secretome from Interleukin-Induced Natural Killer Cells toward Breast Cancer Cell Line by Transwell Assay

“…IL-15 is essential for NK cell survival, differentiation, and proliferation (Anton et al 2015). Improving NK cells cytotoxicity used ILs (IL15, IL18), the result showed that ILs increased TNFα, IFNγ secretion by NK cells (Widowati et al 2020) IL15 induces optimal production of IFN-γ from NK cells, subsequently induce apoptosis of the NK cells toward cancer cells (Ross and Caligiuri 1997;Widowati et al 2020). The human MHC class I-negative of small cell lung cancer cell line (N592) genetically engineered to secrete IL-15, N592/IL-15, showed a reduced tumor growth rate (Orengo et al 2003).…”

“…This result was validated previous research that activated NK cells released higher levels of IFN-γ, TNF-α, Prf1, and GzmB compared to non-induced NK cells. IL2, IL15, and IL18 increased the secretion of IFN-γ, TNF-α, Prf1, and GzmB by coculture cells (Widowati et al 2020). IL15 in NK cell controls as well survival of mature NK cells in the periphery (Marçais et al 2013;Widowati et al 2020), mediated by up-regulation of anti-apoptotic bcl2 family members and down regulation of apoptotic (Marçais et al 2013).…”

“…IL2, IL15, and IL18 increased the secretion of IFN-γ, TNF-α, Prf1, and GzmB by coculture cells (Widowati et al 2020). IL15 in NK cell controls as well survival of mature NK cells in the periphery (Marçais et al 2013;Widowati et al 2020), mediated by up-regulation of anti-apoptotic bcl2 family members and down regulation of apoptotic (Marçais et al 2013). The production of TNF-α, IFN-γ, Prf1, GzmB increased when the ratio of NK cells and hWJMSCs was high (Widowati et al 2019).…”

“…The quantitative determination of GzmB in the transwell-treatment, conditioned medium from NK cells from upper chamber and conditioned medium from MCF7 was performed using ELISA Kit Human Granyme-B (Human ELISA KIT, ElabSci E-EL-H1617) followed the manufactur protocol. Absorbance was read at 450 nm using spectrophotometer (Safta et al 2015;Widowati et al 2018Widowati et al , 2020.…”