Immunotherapeutic approaches to epithelial to mesenchymal transition pathway in THP-1 deri̇ved macrophage and A549 lung cancer co-culture model

Lung cancer is the leading cause of cancer-related deaths and the cause of death is largely metastasis. Initiation and metastasis of lung cancer, the interaction with the microenvironment of cancer cells and is primarily dependent on tumor associated macrophages. Epithelial-mesenchymal transition (EMT) plays an important role in the cancer metastasis. In our study, in order to clarify the EMT related role of macrophages in lung cancer, in vitro co-culture models were designed in A549 cells with M1, M2a and M2c macrophages polarized to phenotype different from THP-1 human monocyte cells. In our study, we aimed to determine the effects of bortezomib and ixazomib 'inhibitors of NF-kB' and M1, M2a and M2c polarized macrophages on anti-proliferative, anti-apoptotic and EMT mechanisms in A549 lung cancer co-culture. We also determined the antiproliferative effects of bortezomib and ixazomib on A549 cells in both 2D and 3D cultures. As a result, it was determined that anti-proliferative and anti-apoptotic effects were high in A549 cells in co-culture with M1 macrophage. In addition, it has been determined that M1 macrophage causes increased anti-proliferative and anti-apoptotic effects of bortezomib and ixazomib. Our results have been demonstrated by increasing the levels of vimentin, fibronectin, NF-kB, CCL-17 and VEGF in A549 cells, reducing the levels of E-cadherin, and inhibiting this effect by ixazomib. Finally, the IC50 value in 3D culture in A549 cells was determined approximately 15 times higher for bortezomib and about 9 times higher for ixazomib than 2D culture medium.