Identification of Siglec-9 as the receptor for MUC16 on human NK cells, B cells, and monocytes.
BACKGROUND
MUC16 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.


RESULTS
Analysis 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.


CONCLUSIONS
Recent 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.
Belisle
Jennifer A
JA
Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI, USA.
Horibata
Sachi
S
Jennifer
Gubbels A A
GA
Petrie
Sarah
S
Kapur
Arvinder
A
André
Sabine
S
Gabius
Hans-Joachim
HJ
Rancourt
Claudine
C
Connor
Joseph
J
Paulson
James C
JC
Patankar
Manish S
MS
D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D015153:Blotting, Western; D018394:CA-125 Antigen / Q000276:immunology / Q000378:metabolism*; D002469:Cell Separation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D019169:Jurkat Cells; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D037102:Lectins / Q000276:immunology / Q000378:metabolism*; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000276:immunology / Q000378:metabolism*; D063265:Sialic Acid Binding Immunoglobulin-like Lectins
D015703:Antigens, CD; D018394:CA-125 Antigen; D037102:Lectins; C451759:MUC16 protein, human; D008565:Membrane Proteins; C412227:SIGLEC9 protein, human; D063265:Sialic Acid Binding Immunoglobulin-like Lectins