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 CD16(pos)/CD56(dim) NK cells, 20-30% of B
cells and > 95% of monocytes. sMUC16 binds to the majority of
the Siglec-9(pos) 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.