Plasminogen Activator Inhibitor 1 Promotes Immunosuppression in Human Non-Small Cell Lung Cancers by Enhancing TGF-Β1 Expression in Macrophage.
BACKGROUND
Plasminogen activator inhibitor-1 (PAI-1) has been regarded as a risk factor for thrombosis and atherosclerosis. Since it has been shown that PAI-1 can activate macrophages through Toll-like receptor-4, we sought to investigate the role of PAI-1 in the tumor microenvironment.


METHODS
The expression and distribution patterns of PAI-1 and transforming growth factor beta (TGF-β) were measured in 60 non-small cell lung cancer (NSCLC) tumors. A statistical correlation analysis was performed between PAI-1 and TGF-β expression and distribution in each tumor. The distribution of tumor-associated macrophages (TAMs) was also measured and its correlation to PAI-1 levels was analyzed. Levels of secreted CCL-17, CCL-22, IL-6 and TGF-β were measured in cell cultures of human macrophage cell lines THP-1 and U937 treated with PAI-1. Levels of secreted PAI-1 were monitored in cell cultures of human NSCLCs cell lines 95D and A549 treated with TGF-β. Secreted proteins were measured in cell culture supernatants using ELISA. Changes in downstream signaling pathways were investigated using western blot.


RESULTS
PAI-1 and TGF-β were found to be overexpressed in human NSCLCs. PAI-1 expression was tightly correlated to TGF-β expression as well as the percentage of TAMs. PAI-1 treatment increased the expression of TAM-associated cytokines and chemokines, including CCL-17, CCL-22, and IL-6. PAI-1 treatment was also observed to enhance TGF-β expression in macrophage cell lines through an IL-6 autocrine/paracrine manner. The effects on TGF-β expression were blocked by NF-κB and STAT3 inhibition. Interestingly, TGF-β also increased levels of secreted PAI-1 in NSCLC cells through SMAD3-dependent signaling, therefore resulting in a feed-forward loop. However, this loop could be blocked by NF-κB, STAT3 and SMAD3 signaling inhibition, as well as treatment with a high concentration of TGF-β.


CONCLUSION
PAI-1 and TGF-β promote NSCLC tumor cells and TAMs and might be valuable targets for cancer immunosuppression.
['Zhu|Chengjun|C|', 'Shen|Hua|H|', 'Zhu|Lingjun|L|', 'Zhao|Feng|F|', 'Shu|Yongqian|Y|']
D002289:Carcinoma, Non-Small-Cell Lung D045744:Cell Line, Tumor D005260:Female D006801:Humans D007108:Immune Tolerance D015850:Interleukin-6 D008168:Lung D008175:Lung Neoplasms D008264:Macrophages D008297:Male D016328:NF-kappa B D017395:Plasminogen Activator Inhibitor 1 D051197:Toll-Like Receptor 4 D053773:Transforming Growth Factor beta1
PAI-1 TGF-β NSCLC TAMs Hegdhr