A cancer vaccine based on fluorine-modified sialyl-Tn induces robust immune responses in a murine model

Abstract

Development of an effective vaccine to target tumor associated carbohydrate antigens, aberrantly expressed on the cell surface of various carcinomas, is an appealing approach toward cancer immunotherapy. However, a major problem of carbohydrate antigens is their poor immunogenicity. Immunization with modified-carbohydrate antigens could improve the immunogenicity and induce cross reaction with the native carbohydrate antigens. In this study, we investigated the antitumor ability of three fluoro-substituted sialyl-Tn (STn) analogues (2, 3, 4) coupled to KLH (keyhole limpet hemocyanin) and studied the mechanism of tumor immunotherapy of the vaccines in a murine model of colon cancer. Vaccination with 4-KLH, in which the two N-acetyl groups of STn are substituted with N-fluoroacetyl groups, could remarkably prolong the survival of tumor-bearing mouse and resulted in a significant reduction in tumor burden of lungs compared with STn-KLH (1-KLH). The vaccine 4-KLH could provoke stronger cytotoxic T lymphocytes immune response, T helper (Th) cell-mediated immune response and an earlier-stage Th1 immune response than 1-KLH, thus breaking immune tolerance and generating a therapeutic response. The 4-KLH vaccine induced strong tumor-specific anti-STn antibodies which could mediate complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity against human tumor cells. Moreover, in the absence of adjuvant, 4-KLH still elicited stronger immune responses than 1-KLH. Our data suggested that 4-KLH is superior in tumor prevention. The strategic hapten fluorination may be a potential approach applicable to the vaccines development for the cancer immunotherapy.

Glycoconjugate vaccines: some observations on carrier and production methods

“…As any antigen that is perceived as non-self will be sufficient to induce an immune response, there is a vast array of known proteins at our disposal to use as carrier. For example, keyhole limpet hemocyanin has been used as a carrier for glycoconjugate vaccines against Candida albicans (Liao et al, 2016) and even some cancers with distinct molecular markers (Song, Zheng, Liu, Zhou, & Ye, 2017). Bovine serum albumin (BSA) is a wellcharacterised protein that has also been used, for example against Aspergillus fumigatus (Komarova et al, 2015).…”

Carbohydrate‐based vaccines for oncotherapy

“…Recently, a fluoro‐substituted STn analogue coupled to KLH was found to induce robust immune responses in a tumor‐bearing murine model. This vaccine candidate could mediate complement‐dependent cytotoxicity and antibody‐dependent cell‐mediated cytotoxicity against human tumor cells, and it seemed a superior in tumor prevention . Several STn derivatives with N ‐acetyl modifications were synthesized, they were then incorporated into a MUC1 peptide and were further connected to KLH.…”

“…This vaccine candidate could mediate complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity against human tumor cells, and it seemed a superior in tumor prevention. 204 Several STn derivatives with N-acetyl modifications were synthesized, they were then incorporated into a MUC1 peptide and were further connected to KLH. The evaluation results of the synthetic vaccine conjugates demonstrated that the carbohydrate antigen modification strategy has the potential to improve immunogenicity of natural MUC1 glycopeptides.…”

A combined computational-experimental approach to define the structural origin of antibody recognition of sialyl-Tn, a tumor-associated carbohydrate antigen

“…The disaccharide Neu5Acα2–6GalNAcα1- O -Ser/Thr is a common short O -glycan TACA conjugated to proteins, also referred to as sialyl-Tn (STn; AcSTn). While this is a rare antigen or occluded in normal tissues due to further O -acetylation of the sialic acid (Sia) 3 , it is present in more than 80% of human carcinomas 13 , including those of the pancreas, breast, prostate, ovaries and colorectum 14 , 15 . Cells expressing the STn antigen have reduced adherence to extracellular matrix components, and show higher migration rates, thus promoting metastasis 16 .…”