Potent suppression of natural killer cell response mediated by the ovarian tumor marker CA125.
OBJECTIVE
CA125 expresses specific oligosaccharides that can inhibit the cytotoxicity of human natural killer (NK) cells. The current study was undertaken to determine the ability of CA125 to modulate NK cell-mediated cytotoxicity.


METHODS
CA125 was isolated from OVCAR-3 cells and its purity was determined by ELISA and ultra-sensitive mass spectrometric analysis. Peripheral blood-derived NK were treated with CA125 and standard cytotoxicity assays were performed using 51Cr-labeled K562 cells as targets. The expression of cell surface and intracellular markers on NK cells was determined by either flow cytometry or Western blot analysis.


RESULTS
NK cells incubated with CA125 for 72 h exhibited a 50-70% decrease in the lysis of K562 targets. Incubation with CA125 for 4 h and 24 h had no effect on NK-mediated cytolysis. Inhibition of NK function was observed at CA125 concentrations (10,000-100,000 U/ml) that are expected to be significantly lower than those observed in the tumor microenvironment. Co-stimulation with IL-2 did not abrogate the NK inhibitory response of CA125. CA125 did not reduce proliferation or induce apoptosis of NK cells and alter the expression of p56lck, phospholipase Cgamma1, ZAP70, or CD3zeta. CA125 did, however, induce major downregulation of CD16 and minor decrease in expression of CD94/NKG2A.


CONCLUSIONS
Our ongoing research and recent work performed by other laboratories highlights the potential physiologic role of this mucin. Based on the data presented here, it is likely that the tumor-derived CA125 acts as a suppressor of the immune response that is directed against the ovarian tumors.
Patankar
Manish S
MS
Department of Obstetrics and Gynecology, University of Wisconsin-Madison, 600 Highland Avenue, H4/657 CSC, Madison, WI 53792-6188, USA. patankar@wisc.edu
Jing
Yu
Y
Morrison
Jamie C
JC
Belisle
Jennifer A
JA
Lattanzio
Frank A
FA
Deng
Yuping
Y
Wong
Nyet Kui
NK
Morris
Howard R
HR
Dell
Anne
A
Clark
Gary F
GF
D018394:CA-125 Antigen / Q000276:immunology* / Q000302:isolation & purification / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003470:Culture Media; D003602:Cytotoxicity, Immunologic; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology*; D010051:Ovarian Neoplasms / Q000276:immunology*; D017452:Receptors, IgG / Q000276:immunology
D018394:CA-125 Antigen; D003470:Culture Media; D017452:Receptors, IgG