Structure-based Design of Anti-cancer Vaccines: The Significance of Antigen Presentation to Boost the Immune Response

Abstract

: Immunotherapy, alone or in combination with other therapies, is widely used against cancer. Glycoprotein Mucin 1 (MUC1), which is overexpressed and aberrantly glycosylated in tumor cells, is one of the most promising candidates to engineer new cancer vaccines. In this context, the development of stable antigens that can elicit a robust immune response is mandatory. Here, we describe the design and in vivo biological evaluation of three vaccine candidates based on MUC1 glycopeptides that comprise unnatural elements in their structure. By placing the Tn antigen (GalNAcα-O-Ser/Thr) at the center of the design, the chemical modifications include changes to the peptide backbone, glycosidic linkage, and at the carbohydrate level. Significantly, the three vaccines elicit robust immune responses in mice and produce antibodies that can be recognized by several human cancer cells. In all cases, a link was stablished between the conformational changes induced by the new elements in the antigen presentation and the immune response induced in mice. According to our data, the development of effective MUC1-based vaccines should use surrogates that mimic the conformational space of aberrantly glycosylated MUC1 glycopeptides found in tumors.

The effect of a methyl group on structure and function: Serine vs. threonine glycosylation and phosphorylation

“…A very recent study by the Corzana group reported on the preparation of various vaccines made up of the MUC1/Tn antigen epitope and showed that conformational restriction using a Thr or other unnatural amino acids and/or sugar analogues that maintained a restricted presentation elicited higher antibody titers and bound more efficiently to tumor cells that are known to display that structure. (Asin et al, 2022). This would be considered precisely what was described above: Certain structures must mimic the cell surface presentation much better than others.…”

Targeting Tn-Antigen-Positive Human Tumors with a Recombinant Human Macrophage Galactose C-Type Lectin

“…On the one hand, the administration of glycan-based therapies has been suggested for anticancer vaccination. 41,42 On the other hand, recognition of Tn-positive tumor cells by immune cells may result in immunosuppression, 43,44 by promoting Treg cell differentiation and favoring suppression of T cell activation. Exogenously administered purified MGL could thus be used to compete and reduce the binding of dendritic cells on the Tn-expressing tumor cells, and thus reducing tumor escape.…”

Strategies for Synthesizing and Enhancing the Immune Response of Cancer Vaccines Based on MUC1 Glycopeptide Antigens

“…[69][70] Francisco Corzana et al made a number of chemical modifications to tumor vaccines based on MUC1. [71] They constructed an α-methylserine Tn antigenic variant (MeSer) [72] that was integrated into the most immunogenic PDTRP fragment of MUC1 (Figure 3E). Although this non-natural glycopeptide exhibited good stability in the blood, there was no significant difference in terms of enhancement of antigen immunogenicity compared with natural glycopeptides, perhaps because the additional flexibility of unnatural amino acids was adversely affected.…”