A Potential Immune Deviating Pathway that Protects Human Sperm and Aggressive Tumor Cells.

Abstract

The possibility exists that malignant tumor cells employ the same immune deviating pathways that are used to protect immune privileged sites. Glycoproteins associated with human sperm and seminal plasma express Lewis x and Lewis y carbohydrate sequences presented on N-glycans in a very unusual polyvalent fashion (poly-Lewis x/Lewis y type N-glycans). This observation is relevant because previous studies carried out with variants of the human gastric pathogen Helicobacter pylori confirm that lipopolysaccharides bearing Lewis x and Lewis y sequences bind to the dendritic cell-specific lectin designated DC-SIGN and trigger a signal transduction cascade that diverts the adaptive immune response directed against these variants. Therefore the addition of Lewis x and Lewis y sequences to glycoproteins present in sperm and seminal plasma glycoproteins could play a major role in inhibiting Th1 responses directed against autoantigens present in human semen. The Lewis y sequence is also a very well established human tumor associated carbohydrate antigen that is highly upregulated on >70% of all human cancers of epithelial origin but not on normal adult tissues with the notable exception of the male reproductive system. Until recently, the glycoproteins and the glycan types that carry Lewis antigens on aggressive tumor cells were unknown. A recent study confirmed that the major carrier of Lewis x and Lewis y sequences on human MCF-7 breast cancer cells is CD98hc. An intriguing linkage is that these sequences are also associated with poly-Lewis x/Lewis y type N-glycans that are similar to those found on human sperm and in seminal plasma. In this study, lectin affinity chromatography of human seminal plasma glycoproteins was employed to isolate the major glycoprotein carriers of Lewis x and Lewis y sequences within this fluid. A major band of 75 kDa glycoprotein with the same MW as CD98hc in MCF-7 cells was identified. Minor bands were also detected at 125 and 150 kDa. Glycoproteomic and functional analyses are now underway to determine the identity of these glycoproteins, define their glycosylation state, and analyze their immunological activities. It is well established that human seminal plasma also contains copious amounts of transforming growth factor-β. (TGF-β) and prostaglandin PGE2, two other very potent immunomodulatory factors. Therefore immune privilege in the human male reproductive system could rely primarily on the coordinated expression of these factors and Lewis x and Lewis y sequences in combination with physical boundaries like the blood:testis barrier. Many metastatic tumors express precisely this same combination of factors and Lewis antigens but lack any physical barrier. The absence of such barriers could enable tumor associated antigens to easily escape from malignancies and evoke adaptive responses, unlike autoantigens at immune privileged sites. These observations are consistent with the hypothesis that aggressive tumor cells employ the same immune deviating pathways that are used to protect human sperm in the human male reproductive system. These results are also consistent with the eutherian fetoembryonic defense system hypothesis. (This investigation was supported by a Pilot Study Fund from the Institute of Clinical and Translational Science at the University of Missouri-Columbia, the Breeden-Adams Foundation and the Mission Enhancement Program in Reproductive Biology and Medicine funded by the state of Missouri.) (poster)