Comparison of adjuvant activity of N- and C-terminal domain of gp96 in a Her2-positive breast cancer model

摘要

It has been frequently reported that gp96 acts as a strong biologic adjuvant. Some studies have even investigated adjuvant activity of the gp96 C- or N-terminal domain. The controversy surrounding adjuvant activity of gp96 terminal domains prompted us to compare adjuvant activity of gp96 C- or N-terminal domain toward Her2eu, as DNA vaccine in a Her2eu-positive breast cancer model. To do so, mice were immunized with DNA vaccine consisting of transmembrane and extracellular domain (TM + ECD) of rat Her2eu alone or fused to N- or C-terminal domain of gp96. Treatment with Her2eu fused to N-terminal domain of gp96 resulted in tumor progression, compared to the groups vaccinated with pCT/Her2 or pHer2. Immunological examination revealed that treatment with Her2eu fused to N-terminal domain of gp96 led to significantly lower survival rates, higher interferon-γ secretion, and induced infiltration of CD4+/CD8+ cells to the tumor site. However, it could not induce cytotoxic T lymphocyte activity, did not decrease regulatory T cell percentage at the tumor site, and eventually led to tumor progression. Our results reveal that gp96 N-terminal domain does not have adjuvant activity toward Her2eu. It is also proposed that adjuvant activity and the resultant immune response of gp96 terminal domains may be directed by the antigen applied.