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

Abstract

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 Her2/neu, as DNA vaccine in a Her2/neu-positive breast cancer model. To do so, mice were immunized with DNA vaccine consisting of transmembrane and extracellular domain (TM + ECD) of rat Her2/neu alone or fused to N-or C-terminal domain of gp96. Treatment with Her2/neu fused to Nterminal domain of gp96 resulted in tumor progression, compared to the groups vaccinated with pCT/Her2 or pHer2. Immunological examination revealed that treatment with Her2/neu 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 Her2/neu. It is also proposed that adjuvant activity and the resultant immune response of gp96 terminal domains may be directed by the antigen applied.

The critical roles of endoplasmic reticulum chaperones and unfolded protein response in tumorigenesis and anticancer therapies

“…Taken together, these studies demonstrate that the use of GRP94 as an antitumor vaccination can prevent cancer development. However, GRP94 vaccination in mice appears less promising in the treatment of established tumors 114,116,117 , and clinical trials across various types of tumors suggest that autologous tumor-derived GRP94 vaccination may have limited efficacy 118–121 .…”

Mini-chaperones

“…According to the obtained results, immune-stimulatory properties of different gp96 domains may be affected by the antigen of interest. 49 Even, the reports on the adjuvant activity of C-terminal domain of gp96 are controversial, depending on the antigen. 50,51 The data showed that the construct containing the C-terminal of gp96 fused with Her2/neu, but not the co-administration of the two separated constructs, decreased CD4+CD25+foxp3+ regulatory T cells at the tumor site and enhanced CTL activity as well as IFN-γ secretion.…”