The progression of pancreatic cancer is affected by the surrounding microenvironment which largely consists of cancer associated fibroblasts and infiltrating inflammatory cells, including natural killer (NK) cells. Several studies have suggested that matrix metallopeptidase 9 (MMP-9), a 92-kDa type IV collagenase which is secreted by mesenchymal stem cells (MSC), can significantly downregulate the cytotoxicity of NK cells in vitro by targeting T cells. Indoleamine 2, 3-dioxygenase (IDO) has also been reported to play a role in MSC-mediated immunosuppression by inhibiting NK cell accumulation and suppressing NK cell function. This suggests that MMP-9 and IDO may play similar roles in tumor-induced NK cell dysfunction. Decreased infiltration of inflammatory cells into the tumor microenvironment has been associated with increased expression of COX-2, which is known to promote tumor growth via its major product prostaglandin E2 (PGE2) in a T cell or NK cell-dependent manner. Together, MMP-9, IDO and PGE2 are potent effectors in the interaction between pancreatic cancer cells and NK cells.
Peng Y-P, et al. Elevation of MMP-9 and IDO induced by pancreatic cancer cells mediates natural killer cell dysfunction. BMC Cancer. 2014;14:738.