Mixed‐Up Sugars: Glycosyltransferase Cross‐Reactivity in Cancerous Tissues and Their Therapeutic Targeting

The main categories of glycan changes in cancer are: (1) decreased expression of histo‐blood group A and/or B antigens and increased Lewis‐related antigens, (2) appearance of cryptic antigens, such as Tn and T, (3) emergence of genetically incompatible glycans, such as A antigen expressed in tumors of individuals of group B or O and heterophilic expression of Forssman antigen (FORS1), and (4) appearance of neoglycans. This review focuses on the expression of genetically incompatible A/B/FORS1 antigens in cancer. Several possible molecular mechanisms are exemplified, including missense mutations that alter the sugar specificity of A and B glycosyltransferases (AT and BT, respectively), restoration of the correct codon reading frame of O alleles, and modification of acceptor specificity of AT to synthesize the FORS1 antigen by missense mutations and/or altered splicing. Taking advantage of pre‐existing natural immunity, the potential uses of these glycans for immunotherapeutic targeting will also be discussed. Genetically incompatible and/or cryptic glycans can be expressed in cancer. In humans, both humoral and cellular natural immunity exists against these glycans. The fact that tumors expressing these glycans grow indicates that immunity is not strong enough. However, it can be enhanced by active/passive immunization, for example, using mini‐transfusion of glycan‐expressing red blood cells, which may have the potential to be used for novel cancer immunotherapy.