Enhanced anti-tumor therapeutic efficacy of DNA vaccine by fusing the E7 gene to BAFF in treating human papillomavirus-associated cancer

Abstract

B-cell-activating factor (BAFF) belongs to the tumor necrosis factor family that not only stimulates B and T cells but also counteracts immune tolerance. BAFF is also a type II membrane protein, which is secreted through the endoplasmic reticulum (ER)–Golgi apparatus pathway. Fusing an antigen to BAFF might enhance the presentation of major histocompatibility complex class I molecules. These characteristics represent an opportunity to enhance the antitumor effects of DNA vaccines. Therefore, we fused BAFF to human papillomavirus type 16 E7 as a DNA vaccine and evaluated its antitumor effects. We found that this vaccine increased E7-specific CD8+ T-cell immune responses, engendered major antitumor effects against E7-expressing tumors, and prolonged the survival of the immunized mice. Interestingly, vaccinating B-cell-deficient mice with BAFF–E7 revealed considerable E7-specific CD8+ T-cell immune responses, suggesting that B cells do not contribute to this immune response. Image analysis through confocal fluorescence microscopy revealed that fusing BAFF to E7 targeted the protein to the ER, but not BAFF lacking 128 N-terminal residues that generated a lower number of E7-specific CD8+ T cells in the vaccinated mice. Our data indicated that the ER-targeting characteristic of BAFF is the main factor improving the potency of DNA vaccines.

Effects of B cell–activating factor on tumor immunity

“…Our observation that BAFF may augment therapeutic vaccine responses in whole cell cancer vaccines builds upon the work of Shurin and colleagues, who find that BAFF is vital for the antitumor activity of dendritic vaccines (37). Additionally, BAFF has been previously shown to augment vaccine responses against a number of bacterial and viral antigens (38)(39)(40)(41)(42).…”

Therapeutic DNA Vaccines for Human Papillomavirus and Associated Diseases

“…DNA vaccines encoding the HPV-16 E7 gene linked to an adenoviral E3 signal sequence, IFN-c-induced protein 10 (IP-10), or B-cell activating factor promoted E7 accumulation in the endoplasmic reticulum and enhanced E7-specific CD8+ T-cell response in vaccinated mice. [138][139][140] Fusion of E7 to ER chaperone molecules, such as ER-60, tapasin, and calnexin also enhanced E7-specific T-cell responses and generated protective and therapeutic antitumor effects in vaccinated mice. 141 CRT is a polypeptide chaperone molecule within the ER that aids in antigen presentation through MHC I pathways.…”

Trial watch: DNA-based vaccines for oncological indications

“…This construct generated robust E7-specific CD8 C T cell immunity, which retarded the growth of TC-1 cells in vivo, and prolonged the survival of tumor-bearing mice. 195 Recently, the efficacy of a plasmid encoding a fusion of signal peptide (Sig), a variant of E7 from HPV16 modified at residues 24 and 27 to abrogate its transforming potential and chaperone protein DnaK (dnaK; best known as HSP70) from Mycobacterium tuberculosis (pNGVL4a-Sig/E7(detox)/HSP70) followed by a single boost with a vaccinia virus expressing E6 and E7 (TA-HPV) was monitored in mice bearing TC-1 cells. The cervicovaginal administration of this vaccine improved tumor infiltration with E7-specific CD8 C T cells, increased their expression of a4b7 integrins and C-C motif chemokine receptor 9 (CCR9) (which is required for T-cell homing), and ameliorated tumor control.…”