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MUC16 provides immune protection by inhibiting synapse formation between NK and ovarian tumor cells.

Gubbels JA, Felder M, Horibata S, Belisle JA, Kapur A, Holden H, Petrie S, Migneault M, Rancourt C, Connor JP, Patankar MS - Mol. Cancer (2010)

Bottom Line: Our results indicate that MUC16-mediated inhibition of immune synapse formation is an effective mechanism employed by ovarian tumors to evade immune recognition.The NK cell leukemia cell line (NKL), which does not express KIRs but are positive for DNAM-1 and NKG2D, also conjugated and lysed MUC16-knockdown cells more efficiently than MUC16 expressing controls.The higher csMUC16 levels on the NKL resistant tumor cells correlated with more protection from lysis as compared to target cells that were never exposed to the effectors.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI, USA.

ABSTRACT

Background: Cancer cells utilize a variety of mechanisms to evade immune detection and attack. Effective immune detection largely relies on the formation of an immune synapse which requires close contact between immune cells and their targets. Here, we show that MUC16, a heavily glycosylated 3-5 million Da mucin expressed on the surface of ovarian tumor cells, inhibits the formation of immune synapses between NK cells and ovarian tumor targets. Our results indicate that MUC16-mediated inhibition of immune synapse formation is an effective mechanism employed by ovarian tumors to evade immune recognition.

Results: Expression of low levels of MUC16 strongly correlated with an increased number of conjugates and activating immune synapses between ovarian tumor cells and primary naïve NK cells. MUC16-knockdown ovarian tumor cells were more susceptible to lysis by primary NK cells than MUC16 expressing controls. This increased lysis was not due to differences in the expression levels of the ligands for the activating receptors DNAM-1 and NKG2D. The NK cell leukemia cell line (NKL), which does not express KIRs but are positive for DNAM-1 and NKG2D, also conjugated and lysed MUC16-knockdown cells more efficiently than MUC16 expressing controls. Tumor cells that survived the NKL challenge expressed higher levels of MUC16 indicating selective lysis of MUC16(low) targets. The higher csMUC16 levels on the NKL resistant tumor cells correlated with more protection from lysis as compared to target cells that were never exposed to the effectors.

Conclusion: MUC16, a carrier of the tumor marker CA125, has previously been shown to facilitate ovarian tumor metastasis and inhibits NK cell mediated lysis of tumor targets. Our data now demonstrates that MUC16 expressing ovarian cancer cells are protected from recognition by NK cells. The immune protection provided by MUC16 may lead to selective survival of ovarian cancer cells that are more efficient in metastasizing within the peritoneal cavity and also at overcoming anti-tumor innate immune responses.

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DNAM-1 and NKG2D ligand expression is comparable on csMUC16high expressing OVCAR-3 cells. OVCAR-3 cells were stained for csMUC16 expression, and then NKG2D-Fc or DNAM-1-Fc and an appropriate secondary antibody were added. Cells were initially gated on live single events of tumor cells that were csMUC16low or csMUC16high. The binding of NKG2D-Fc or DNAM-1 to gated csMUC16low (gray line) and csMUC16high (black line) is shown in histogram form. Data is representative of three independent experiments.
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Figure 2: DNAM-1 and NKG2D ligand expression is comparable on csMUC16high expressing OVCAR-3 cells. OVCAR-3 cells were stained for csMUC16 expression, and then NKG2D-Fc or DNAM-1-Fc and an appropriate secondary antibody were added. Cells were initially gated on live single events of tumor cells that were csMUC16low or csMUC16high. The binding of NKG2D-Fc or DNAM-1 to gated csMUC16low (gray line) and csMUC16high (black line) is shown in histogram form. Data is representative of three independent experiments.

Mentions: DNAM-1-Fc or NKG2D-Fc chimeras were added to OVCAR-3 cells and the cells were gated for high or low csMUC16 expression (Figure 2). OVCAR-3 cells expressing low or high csMUC16 expressed comparable levels of DNAM-1 and NKG2D ligands (Figure 2). These data indicate that differences in expression of DNAM-1 or NKG2D ligands was not a factor in the ability of NK cells to conjugate to OVCAR-3 cells.


MUC16 provides immune protection by inhibiting synapse formation between NK and ovarian tumor cells.

Gubbels JA, Felder M, Horibata S, Belisle JA, Kapur A, Holden H, Petrie S, Migneault M, Rancourt C, Connor JP, Patankar MS - Mol. Cancer (2010)

DNAM-1 and NKG2D ligand expression is comparable on csMUC16high expressing OVCAR-3 cells. OVCAR-3 cells were stained for csMUC16 expression, and then NKG2D-Fc or DNAM-1-Fc and an appropriate secondary antibody were added. Cells were initially gated on live single events of tumor cells that were csMUC16low or csMUC16high. The binding of NKG2D-Fc or DNAM-1 to gated csMUC16low (gray line) and csMUC16high (black line) is shown in histogram form. Data is representative of three independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2818693&req=5

Figure 2: DNAM-1 and NKG2D ligand expression is comparable on csMUC16high expressing OVCAR-3 cells. OVCAR-3 cells were stained for csMUC16 expression, and then NKG2D-Fc or DNAM-1-Fc and an appropriate secondary antibody were added. Cells were initially gated on live single events of tumor cells that were csMUC16low or csMUC16high. The binding of NKG2D-Fc or DNAM-1 to gated csMUC16low (gray line) and csMUC16high (black line) is shown in histogram form. Data is representative of three independent experiments.
Mentions: DNAM-1-Fc or NKG2D-Fc chimeras were added to OVCAR-3 cells and the cells were gated for high or low csMUC16 expression (Figure 2). OVCAR-3 cells expressing low or high csMUC16 expressed comparable levels of DNAM-1 and NKG2D ligands (Figure 2). These data indicate that differences in expression of DNAM-1 or NKG2D ligands was not a factor in the ability of NK cells to conjugate to OVCAR-3 cells.

Bottom Line: Our results indicate that MUC16-mediated inhibition of immune synapse formation is an effective mechanism employed by ovarian tumors to evade immune recognition.The NK cell leukemia cell line (NKL), which does not express KIRs but are positive for DNAM-1 and NKG2D, also conjugated and lysed MUC16-knockdown cells more efficiently than MUC16 expressing controls.The higher csMUC16 levels on the NKL resistant tumor cells correlated with more protection from lysis as compared to target cells that were never exposed to the effectors.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI, USA.

ABSTRACT

Background: Cancer cells utilize a variety of mechanisms to evade immune detection and attack. Effective immune detection largely relies on the formation of an immune synapse which requires close contact between immune cells and their targets. Here, we show that MUC16, a heavily glycosylated 3-5 million Da mucin expressed on the surface of ovarian tumor cells, inhibits the formation of immune synapses between NK cells and ovarian tumor targets. Our results indicate that MUC16-mediated inhibition of immune synapse formation is an effective mechanism employed by ovarian tumors to evade immune recognition.

Results: Expression of low levels of MUC16 strongly correlated with an increased number of conjugates and activating immune synapses between ovarian tumor cells and primary naïve NK cells. MUC16-knockdown ovarian tumor cells were more susceptible to lysis by primary NK cells than MUC16 expressing controls. This increased lysis was not due to differences in the expression levels of the ligands for the activating receptors DNAM-1 and NKG2D. The NK cell leukemia cell line (NKL), which does not express KIRs but are positive for DNAM-1 and NKG2D, also conjugated and lysed MUC16-knockdown cells more efficiently than MUC16 expressing controls. Tumor cells that survived the NKL challenge expressed higher levels of MUC16 indicating selective lysis of MUC16(low) targets. The higher csMUC16 levels on the NKL resistant tumor cells correlated with more protection from lysis as compared to target cells that were never exposed to the effectors.

Conclusion: MUC16, a carrier of the tumor marker CA125, has previously been shown to facilitate ovarian tumor metastasis and inhibits NK cell mediated lysis of tumor targets. Our data now demonstrates that MUC16 expressing ovarian cancer cells are protected from recognition by NK cells. The immune protection provided by MUC16 may lead to selective survival of ovarian cancer cells that are more efficient in metastasizing within the peritoneal cavity and also at overcoming anti-tumor innate immune responses.

Show MeSH
Related in: MedlinePlus