Abstract
BackgroundMUC16 is a cell surface mucin expressed at high levels by epithelial ovarian tumors. Following proteolytic cleavage, cell surface MUC16 (csMUC16) is shed in the extracellular milieu and is detected in the serum of cancer patients as the tumor marker CA125. csMUC16 acts as an adhesion molecule and facilitates peritoneal metastasis of ovarian tumors. Both sMUC16 and csMUC16 also protect cancer cells from cytotoxic responses of natural killer (NK) cells. In a previous study we demonstrated that sMUC16 binds to specific subset of NK cells. Here, we identify the csMUC16/sMUC16 binding partner expressed on immune cells.ResultsAnalysis of immune cells from the peripheral blood and peritoneal fluid of ovarian cancer patients indicates that in addition to NK cells, sMUC16 also binds to B cells and monocytes isolated from the peripheral blood and peritoneal fluid. I-type lectin, Siglec-9, is identified as the sMUC16 receptor on these immune cells. Siglec-9 is expressed on approximately 30-40% of CD16pos/CD56dim NK cells, 20-30% of B cells and >95% of monocytes. sMUC16 binds to the majority of the Siglec-9pos NK cells, B cells and monocytes. sMUC16 is released from the immune cells following neuraminidase treatment. Siglec-9 transfected Jurkat cells and monocytes isolated from healthy donors bind to ovarian tumor cells via Siglec-9-csMUC16 interaction.ConclusionsRecent studies indicate that csMUC16 can act as an anti-adhesive agent that blocks tumor-immune cell interactions. Our results demonstrate that similar to other mucins, csMUC16 can also facilitate cell adhesion by interacting with a suitable binding partner such as mesothelin or Siglec-9. Siglec-9 is an inhibitory receptor that attenuates T cell and NK cell function. sMUC16/csMUC16-Siglec-9 binding likely mediates inhibition of anti-tumor immune responses.
Highlights
MUC16 is a membrane spanning mucin that is expressed on ovarian, endometrial, tracheal, and ocular surface epithelial cells [1,2,3,4]
This mucin is initially expressed on the surface and shed in the extracellular milieu following proteolytic cleavage [5,6,7]. cell surface MUC16 (csMUC16) carries a ~12,000 amino acid N-terminal region, a Variable Number of Tandem Repeat (VNTR) domain composed of 60 tandem repeats of 156 amino acids, and a 256 amino acid cytoplasmic tail [7,8,9]
Because sMUC16 binds only to subsets of CD16pos/CD56dim natural killer (NK) cells and inhibits their cytolytic activity, we postulated that sMUC16 is likely a ligand of an inhibitory receptor on NK cells
Summary
MUC16 is a membrane spanning mucin that is expressed on ovarian, endometrial, tracheal, and ocular surface epithelial cells [1,2,3,4]. This mucin is initially expressed on the surface (cell surface MUC16, csMUC16) and shed (shed MUC16, sMUC16) in the extracellular milieu following proteolytic cleavage [5,6,7]. Cell surface MUC16 (csMUC16) is shed in the extracellular milieu and is detected in the serum of cancer patients as the tumor marker CA125. We identify the csMUC16/sMUC16 binding partner expressed on immune cells
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