Effective Tumor Protection by a Tumor-Associated Mucin-1 Glycopeptide-Based Conjugate Vaccine in a Spontaneous Mouse Breast Cancer Model

Abstract

Human mucin-1 (MUC1) is an attractive tumor antigen due to its high expression levels on tumor cells and its important roles in tumor development. Due to the aberrant glycosylation of MUC1 on tumor cells, tumor-associated MUC1 (tMUC1) has a shortened O-glycan attached on the peptide backbone, distinguishing it from its counterpart on normal cells. Preclinical evaluation of tMUC1-based vaccine candidates typically involved the immunization of mice that are tumor-free. However, tumor development is often associated with immune suppression. To better mimic clinical conditions encountered in cancer treatment, a breast cancer mouse model was built by crossing mouse mammary tumor virus (MMTV)-polyoma middle T (PyMT) mice with human MUC1 transgenic (MUC1.Tg) mice. The resulting female double-transgenic mice (MUC1/MMTV) spontaneously develop palpable breast cancer from 6 weeks of age. A promising vaccine candidate composed of a short 9-amino-acid Thomsen-nouveau (Tn) antigen containing tMUC1 glycopeptide conjugated with bacteriophage Qβ was evaluated in MUC1/MMTV mice. The vaccine was found to be immunogenic and capable of inducing high levels of anti-tMUC1 IgG antibody responses. The antibodies were selective toward both the glycan and the peptide sequence of tMUC1, as deciphered from a glycopeptide microarray study. Furthermore, the induced antibodies bound tumor cells in a MUC1-dependent manner and could kill a range of tumor cells via complement-dependent cytotoxicity. Vaccination with a Qβ-tMUC1 conjugate significantly prolonged the survival of MUC1/MMTV mice, with 83% of treated MUC1/MMTV mice outliving the control group. The Qβ-tMUC1 vaccine exhibited promising results in an aggressive and rapidly growing spontaneous tumor model, laying the groundwork for its clinical translation to human patients.