Abstract
We explored the effect of a recombinant mucin1-maltose-binding protein vaccine, including immunization cycles of recombinant mucin1-maltose-binding protein (MUC1-MBP) and CpG 2006 on T cell responses to human MUC1-overexpressing mouse melanoma B16 cells (B16-MUC1) melanoma in mice. We found that the vaccine had a significant antitumor effect, with the most obvious tumor-suppressive effect being observed in mice immunized five times. After more than five immunizations, the tumor inhibition rate decreased from 81.67% (five immunizations) to 43.67% (eight immunizations). To study the possible mechanism, Mucin-1(MUC1)-specific antibodies, IFN-γ secretion by lymphocytes, and cytotoxic T lymphocyte (CTL) cytotoxicity were measured by enzyme-linked immunosorbent assay (ELISA) and a real-time cell analyzer (RTCA). T cell subsets and immunosuppressive cells in the mouse spleen and tumor microenvironment were analyzed by FACS. These results showed that five immunizations activated MUC1-specific Th1 and CTL and reduced the ratio of myeloid-derived suppressor cells (MDSCs) and Th17 in mice more significantly than eight immunizations, indicating that excessive frequency of the immune cycle leads to the increased numbers of immunosuppressive cells and decreased numbers of immunostimulatory cells, thereby inhibiting antitumor immune activity. This data provide an experimental foundation for the clinical application of a recombinant MUC1-MBP vaccine.
Highlights
Cancer vaccines are designed to amplify tumor-specific T cell responses through active immunization targeting tumor antigen; they are vital tools for effective cancer immunotherapy
Compared with that in the negative control (NC) group, the CD11b+Gr1+ cell percentage in the spleen and the Tumor Microenvironment (TME) was decreased 8.52-fold and 2.75-fold, respectively, in mice immunized five times with the vaccine, whereas it was decreased 4.32-fold and 1.51-fold, respectively, in mice immunized eight times (Figure 5B–D). These results suggested that the recombinant MUC1-maltose-binding protein (MBP) vaccine enhanced the antitumor effect by reversing the immunosuppressive state of the TME and that excessive immunization cycles increased the proportion of immunosuppressive cells
Similar to the findings in the preventive mouse model, these results showed that five immunizations with the recombinant MUC1-MBP vaccine more significantly inhibited B16-MUC1 melanoma growth than eight immunizations in the therapeutic mouse model, and that this greater inhibition was accompanied by a higher IgG2c/IgG1 ratio, more MUC1-specific lymphocyte proliferation, higher IFN-γ secretion by lymphocytes, and higher cytotoxic T lymphocyte (CTL) cytotoxicity (Figure 6B–H)
Summary
Cancer vaccines are designed to amplify tumor-specific T cell responses through active immunization targeting tumor antigen; they are vital tools for effective cancer immunotherapy. MUC1 is abnormally overexpressed and incompletely glycosylated in tumor cells, making it an ideal target for tumor immunotherapy. Various MUC1-targeting tumor vaccines including peptide/protein vaccines, glycopeptides vaccines, DNA vaccines, and dendritic cell (DC) vaccines have been developed. More than sixty such vaccines have entered the clinical trial stage, of which four have entered phase III clinical trials. The disadvantage of peptide/protein vaccines is they do not induce a strong T cell response, which can only be produced in the presence of a suitable adjuvant
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