The immunomodulating roles of glycoproteins in epithelial ovarian cancer

Abstract

The complexity of the immune system demands an intricate defense mechanism by tumors. Ovarian and other tumors employ specific glycoproteins and the associated glycan sequences to modulate immune responses. Glycoproteins enable tumor cells that express or secrete these molecules to evade immune cell attack and induce the immune system to promote tumor growth. This review focuses first on the immune environment in ovarian cancer, and the mechanisms of activation and inhibition that immune cells undergo in order to either attack or ignore a target cell. Next we illustrate the immunomodulatory roles of ovarian cancer-associated glycans and glycoproteins in 1. preventing immune synapse formation, 2. serving as ligands of immune cell receptors, 3. scavenging cytokines and chemokines, and 4. participating in the formation of autoantibodies against the tumor. The importance of these immunomodulating strategies from the view points of understanding the tumor immunology of ovarian tumors, potential origin of such mechanisms, and specific strategies to circumvent the glycoconjugate-mediated suppression of immune responses is discussed in this review.

Figure 1

NK immune synapse. Localization of actin (red) at the contact site between NKL (an NK leukemia cell line) and K562 (target) cells is shown in the left panel. Nucleus stained with DAPI (blue) and perforin (green) is in transition towards the synapse. Recruitment of LFA (green) to the contact site is shown in the right panel.

Figure 2

Recruitment of perforin granules to the NK immune synapse. Synapse between K562 cells (labeled with phalloidin to stain actin, red) and NKL (NK cell leukemia cell line) is shown. Perforin granules (green) are recruited to the synapse. Nucleus is stained with DAPI (blue).

Figure 3

Reduced susceptibility of ovarian tumor cells to NK cell mediated lysis. Ability of NK cells derived from healthy donor peripheral blood to lyse the ovarian tumor cell line OVCAR-3 in comparison to the NK cell susceptible cell line, K562, is shown. Cytotoxicity was determined in a 4 h chromium release assay.

Figure 4

Model for MUC16 induced NK cell suppression. MUC16 binding to Siglec-9 leads to phosphorylation of proximal ITIM (yellow box) of the receptor and subsequently phosphorylation and activation of SHP-1 and/or SHP-2. SHP-1 and SHP-2 are phosphatases that dephosphorylate Vav-1 and other signaling molecules. As a result, polymerization of actin, polarization of actin associated proteins (WASp, WIP, Myosin II), LFA-1, and perforin granules is not achieved. Lack of activating synapse formation leads to protection of the tumor cell. csMUC16-Siglec-9 binding triggers an inhibitory immune synapse that protects the tumor cells from NK cell attack. MUC16 binding to Siglec-9 upregulates IL-10 and other Th2-type cytokines that inhibit the anti-tumor immune responses.