The Development of Vaccines from Synthetic Tumor‐Associated Mucin Glycopeptides and their Glycosylation‐Dependent Immune Response

Abstract

Tumor-associated carbohydrate antigens are overexpressed as altered-self in most common epithelial cancers. Their glycosylation patterns differ from those of healthy cells, functioning as an ID for cancer cells. Scientists have been developing anti-cancer vaccines based on mucin glycopeptides, yet the interplay of delivery system, adjuvant and tumor associated MUC epitopes in the induced immune response is not well understood. The current state of the art suggests that the identity, abundancy and location of the glycans on the MUC backbone are all key parameters in the cellular and humoral response. This review shares lessons learned by us in over two decades of research in glycopeptide vaccines. By bridging synthetic chemistry and immunology, we discuss efforts in designing synthetic MUC1/4/16 vaccines and focus on the role of glycosylation patterns. We provide a brief introduction into the mechanisms of the immune system and aim to promote the development of cancer subunit vaccines.

Alum Adjuvant and Built-in TLR7 Agonist Synergistically Enhance Anti-MUC1 Immune Responses for Cancer Vaccine

“…Tumor-associated antigen mucin 1 (MUC1) is overexpressed on many human epithelial tumor tissues, such as breast, ovarian, and prostate carcinomas, which makes it an attractive target for tumor immunotherapy (1,2). MUC1 contains a variable number of tandem repeat (VNTR) sequence (HGVTSAPDTRPAPGSTAPPA), and five potential O-glycosylation sites are located on the threonines and serines of the tandem repeat sequence (3)(4)(5). In normal cells, MUC1 glycoproteins are expressed in a polarized fashion, whereas MUC1 glycoproteins in tumor cells are overexpressed with much less glycosylation, present all over the cell surface, and show an unpolarized fashion (6,7).…”

“…MUC1 glycopeptide from VNTR sequence was often used as the antigen for the MUC1-targeted antitumor vaccines (8)(9)(10)(11)(12)(13). However, due to the weak immunogenicity of MUC1 glycopeptide, appropriate immune stimulators or carriers are necessary in vaccine designs (4,14).…”

Glycoconjugate Nanoparticle-Based Systems in Cancer Immunotherapy: Novel Designs and Recent Updates

“…Not surprisingly, this design strategy has been coopted for the construction of cancer vaccines to tumor glycan-based antigens ( 80 , 82 – 97 ). However, glycopeptides derived from cell surface proteins containing TACAs (or other immunogenic glycans) can also be presented to T-cells and the sugar can either contribute or detract from MHC binding ( 85 , 98 – 110 ). Discovered about 25 years ago, another set of MHC-II-like antigen presenting molecules, the CD1 family (CD1a-CD1e), has been shown to present cellular and foreign glycolipid antigens to either γδT-cells or Natural Killer T-cells (NKT cells).…”

“…Provided here is a recompilation (not comprehensive)! of reviews only from 2021 that directs the reader to some of this work ( 24 – 27 , 78 , 82 , 110 , 239 – 246 ).…”

Integrated Chemoenzymatic Approach to Streamline the Assembly of Complex Glycopeptides in the Liquid Phase

“…Glycosylation, a common but complicated post-translational modification, is implicated in diverse physiological and pathological activities including cell adhesion and signaling, bacterial and viral infections, immune evasions, and cancer metastasis. − Majority of the human proteins are glycosylated, and biological functions of glycopeptides are realized by the collaborative effects of both the glycan structure and peptide sequence. , Although elegant synthesis methods − and advanced analysis technologies for glycomics and proteomics , have been established, the precise functional studies of glycopeptides are still impeded by lack of robust and cost-effective synthetic methods to prepare a wide range of structurally well-defined glycopeptides. These compounds can serve as probes for elucidating their biosynthesis mechanisms and standards for identifying accurate structures of glycopeptides in complicated biological mixtures and offer opportunities to conduct high-throughput microarray analysis for binding studies, − which could contribute to developing therapeutic agents and vaccines. − …”