Aberrant Glycosylation as Immune Therapeutic Targets for Solid Tumors

SIMPLE SUMMARY: Glycosylation is one of the most pivotal post-translational modifications on all types of biomolecules for the formation of glycoproteins, glycolipids, and glycoRNAs in a tissue-type specific manner. Normal glycans participate in biological events such as development, metabolism, differentiation, and immunity in mammalian cells. In cancers, the altered glycosylation, known as tumor-associated carbohydrate antigens (TACAs), play important roles in facilitating tumor formation, progression, and metastasis. Recent studies also reveal novel roles of TACAs in facilitating the vulnerable tumor microenvironment through the interaction of glycan binding receptors expressed on immune cells. TACAs are specific and expressed on different cell surface molecules in a cancer type-specific manner. Thereby, TACAs are potential tumor glyco-biomarkers, glycoimmune checkpoints, and therapeutics. In this review, we summarize the established and most promising immunotherapy-targeting TACAs such as monoclonal antibody therapy including glycoengineered humanized antibody and antibody-drug conjugates (ADC), chimeric antigen receptor T-cell (CART) therapy, and vaccination in recent clinical trials. ABSTRACT: Glycosylation occurs at all major types of biomolecules, including proteins, lipids, and RNAs to form glycoproteins, glycolipids, and glycoRNAs in mammalian cells, respectively. The carbohydrate moiety, known as glycans on glycoproteins and glycolipids, is diverse in their compositions and structures. Normal cells have their unique array of glycans or glycome which play pivotal roles in many biological processes. The glycan structures in cancer cells, however, are often altered, some having unique structures which are termed as tumor-associated carbohydrate antigens (TACAs). TACAs as tumor biomarkers are glycan epitopes themselves, or glycoconjugates. Some of those TACAs serve as tumor glyco-biomarkers in clinical practice, while others are the immune therapeutic targets for treatment of cancers. A monoclonal antibody (mAb) to GD2, an intermediate of sialic-acid containing glycosphingolipids, is an example of FDA-approved immune therapy for neuroblastoma indication in young adults and many others. Strategies for targeting the aberrant glycans are currently under development, and some have proceeded to clinical trials. In this review, we summarize the currently established and most promising aberrant glycosylation as therapeutic targets for solid tumors.