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


CONCLUSIONS
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.
Gubbels
Jennifer A A
JA
Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI, USA.
Felder
Mildred
M
Horibata
Sachi
S
Belisle
Jennifer A
JA
Kapur
Arvinder
A
Holden
Helen
H
Petrie
Sarah
S
Migneault
Martine
M
Rancourt
Claudine
C
Connor
Joseph P
JP
Patankar
Manish S
MS
D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D018394:CA-125 Antigen / Q000276:immunology*; D002448:Cell Adhesion; D002452:Cell Count; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival; D019610:Cytoprotection / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D005260:Female; D055785:Gene Knockdown Techniques; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D054992:Immunological Synapses / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000473:pathology; D008024:Ligands; D008565:Membrane Proteins / Q000276:immunology*; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000473:pathology; D000098862:T Lineage-Specific Activation Antigen 1
D000945:Antigens, Differentiation, T-Lymphocyte; D018394:CA-125 Antigen; D000098862:T Lineage-Specific Activation Antigen 1; D015395:Histocompatibility Antigens Class I; C527085:KLRK1 protein, human; D008024:Ligands; C451759:MUC16 protein, human; D008565:Membrane Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K