Abstract
The tumor-associated antigen mucin 1 (MUC1) is an attractive target of antitumor vaccine, but its weak immunogenicity is a big challenge for the development of vaccine. In order to enhance immune responses against MUC1, herein, we conjugated small molecular toll-like receptor 7 agonist (TLR7a) to carrier protein BSA via MUC1 glycopeptide to form a three-component conjugate (BSA-MUC1-TLR7a). Furthermore, we combined the three-component conjugate with Alum adjuvant to explore their synergistic effects. The immunological studies indicated that Alum adjuvant and built-in TLR7a synergistically enhanced anti-MUC1 antibody responses and showed Th1-biased immune responses. Meanwhile, antibodies elicited by the vaccine candidate effectively recognized tumor cells and induced complement-dependent cytotoxicity. In addition, Alum adjuvant and built-in TLR7a synergistically enhanced MUC1 glycopeptide-specific memory CD8+ T-cell immune responses. More importantly, the vaccine with the binary adjuvant can significantly inhibit tumor growth and prolong the survival time of mice in the tumor challenge experiment. This novel vaccine construct provides an effective strategy to develop antitumor vaccines.
Highlights
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 glycopeptide (GVTSAPDTRPAPG, 13aa) from the variable number of tandem repeat (VNTR) of MUC1 glycoprotein was used as an antigen, which was synthesized through the solid-phase peptide synthesis (SPPS) with Rink Amide-AM Resin (Scheme 1A)
We report for the first time that the self-adjuvanting protein conjugate is combined with Alum adjuvant in MUC1targeted antitumor vaccine, which induced potent immune responses
Summary
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]. The carrier proteins provide multiple Th and Tc epitopes that could synergistically activate the adaptive immune response [14, 46] Based on these considerations, we covalently conjugated TLR7 agonist (TLR7a) to MUC1 glycopeptide through solid-phase synthesis method (SPPS) in our vaccine design (Scheme 1A). The glycopeptide-adjuvant conjugate MUC1-TLR7a was covalently linked to the carrier protein BSA through the squaric acid diethyl ester method to form a three-component conjugate (BSA-MUC1TLR7a). The BSAMUC1-TLR7a conjugate was combined with Alum adjuvant to determine whether they could synergistically enhance the antiMUC1-specific immune responses (Figure 1). This is the first time to introduce Alum adjuvant to the self-adjuvanting protein conjugate in the MUC1-targeted antitumor vaccine
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