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MUC16 provides immune protection by inhibiting synapse formation between NK and ovarian tumor cells
Jennifer A A Gubbels1, Mildred Felder, Sachi Horibata
1Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI, USA.
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.
Insights
MUC16 protein on ovarian cancer cells prevents immune synapse formation with NK cells. This MUC16 shield helps tumors evade immune attack, promoting metastasis and survival.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Cancer cells employ immune evasion strategies to avoid detection and destruction.
- Immune synapse formation, crucial for immune detection, requires direct contact between immune cells and targets.
- MUC16, a large mucin on ovarian tumor cells, was investigated for its role in immune evasion.
Purpose of the Study:
- To investigate the role of MUC16 in inhibiting immune synapse formation between NK cells and ovarian tumor cells.
- To determine if MUC16 expression influences NK cell-mediated tumor cell lysis.
- To understand the mechanism by which MUC16 contributes to ovarian cancer immune evasion.
Main Methods:
- Assessing immune synapse formation and NK cell conjugation with MUC16-expressing and MUC16-knockdown ovarian tumor cells.
- Measuring NK cell-mediated tumor cell lysis using primary NK cells and the NKL cell line.
- Analyzing the expression of NK cell activating receptor ligands (DNAM-1, NKG2D) and MUC16 levels on surviving tumor cells.
Main Results:
- Low MUC16 expression correlated with increased NK cell conjugates and immune synapses.
- MUC16-knockdown ovarian tumor cells showed increased susceptibility to NK cell lysis.
- Tumor cells surviving NK cell attack exhibited higher MUC16 levels, indicating selective lysis of MUC16(low) targets.
Conclusions:
- MUC16 expression on ovarian cancer cells protects them from NK cell recognition and lysis.
- MUC16-mediated immune protection may facilitate tumor metastasis and survival against anti-tumor immune responses.
- MUC16 acts as a shield, enabling ovarian tumors to evade innate immunity.
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