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

Molecular Cancer

Research

Claudine Rancourt¹  Martine Migneault¹  Joseph P Connor²  Manish S Patankar²  Jennifer A Belisle²  Sarah Petrie²  Mildred Felder²  Jennifer AA Gubbels²  Helen Holden²  Sachi Horibata²  Arvinder Kapur² 

[1] Department of Microbiology and Infectiology, Universite de Sherbrooke, Sherbrooke, Canada;Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, USA;

关键词: Ovarian Cancer Cell;    Ovarian Tumor;    NKG2D Ligand;    Ovarian Tumor Cell;    Immune Synapse;   

DOI  :  10.1186/1476-4598-9-11

 received in 2009-08-10, accepted in 2010-01-20,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundCancer 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.ResultsExpression 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 MUC16low 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.ConclusionMUC16, 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.

【 授权许可】

Unknown   
© Gubbels et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.