Matrix Metalloproteinases in Cytotoxic Lymphocytes Impact on Tumour Infiltration and Immunomodulation

To efficiently combat solid tumours, endogenously or adoptively transferred cytotoxic T cells and natural killer (NK) cells, need to leave the vasculature, traverse the interstitium and ultimately infiltrate the tumour mass. During this locomotion and migration in the three dimensional environment many obstacles need to be overcome, one of which is the possible impediment of the extracellular matrix. The first and obvious one is the sub-endothelial basement membrane but the infiltrating cells will also meet other, both loose and tight, matrix structures that need to be overridden. Matrix metalloproteinases (MMPs) are believed to be one of the most important endoprotease families, with more than 25 members, which together have function on all known matrix components. This review summarizes what is known on synthesis, expression patterns and regulation of MMPs in cytotoxic lymphocytes and their possible role in the process of tumour infiltration. We also discuss different functions of MMPs as well as the possible use of other lymphocyte proteases for matrix degradation

Effects of IL-2 on MMP Expression in Freshly Isolated Human NK Cells and the IL-2-independent NK Cell Line YT

Interleukin-2 is an important activation factor for natural killer (NK) cells but its effect on NK cell matrix metalloproteinases (MMP) production and matrix degradation is less well investigated. We have used freshly isolated human NK cells and the IL-2-independent NK cell line, YT, to investigate the effects of IL-2 stimulation on NK cell invasion of Matrigel and on MMP expression and production. In YT cells, we found opposing early and late effects of IL-2 stimulation with an early (2 h) increase in MMP-9 protein level and enhanced migration in the Matrigel invasion assay and by 30 hours a decreased mRNA expression of MMP-2, MMP-9, MMP-13, MT3-MMP, and MT6-MMP. We also found a preculture period of 48 hours with IL-2 to negatively affect YT cell migration. We furthermore found that freshly isolated human NK cells Matrigel invasion was MMP-dependent and it increased in response to IL-2. Importantly, in freshly isolated human NK cells we did not see a downregulation of MMPs after 24 hours IL-2 stimulation, but instead a significant upregulation of MT6-MMP mRNA. Because of the cellular localisation of MT6-MMP, which ensures a focalized proteolytic activity, and its high expression compared with the other MMPs in freshly isolated human NK cells makes it of interest to study further.Surgical oncolog