Treatment of established tumors with a novel vaccine that enhances major histocompatibility class II presentation of tumor antigen.

TLDR

MHC class II presentation to CD4⁺ T cells is essential for antitumor immunity. The study aimed to evaluate whether a LAMP‑1–targeted E7 chimera could improve MHC class II presentation and protect mice from E7⁺ TC‑1 tumors. Recombinant vaccinia vectors expressing the Sig/E7/LAMP‑1 chimera were used to target E7 to endosomal/lysosomal compartments, enhancing MHC class II presentation and enabling in vivo tumor protection studies. Vaccination with Sig/E7/LAMP‑1 vaccinia achieved 80 % tumor‑free survival and cured established TC‑1 tumors, whereas wild‑type E7 vaccinia had no effect, demonstrating the therapeutic advantage of antigen rerouting.

Abstract

Presentation of antigenic peptides by MHC class II molecules to CD4+ T cells is critical to the generation of antitumor immunity. In an attempt to enhance MHC class II antigen processing, we linked the sorting signals of the lysosome-associated membrane protein (LAMP-1) to the cytoplasmic/nuclear human papilloma virus (HPV-16) E7 antigen, creating a chimera (Sig/E7/LAMP-1). Previously, we found that expression of this chimera in vitro and in vivo with a recombinant vaccinia vector targeted E7 to endosomal and lysosomal compartments and enhanced MHC class II presentation to CD4+ T cells compared to vaccinia expressing wild-type E7. In the current study, we tested these recombinant vaccinia for in vivo protection against an E7+ tumor, TC-1, which was derived from primary epithelial cells of C57BL/6 mice cotransformed with HPV-16 E6 and E7 and c-Ha-ras oncogenes. All mice vaccinated with 1 x 10(7) plaque-forming units of wild-type E7-vaccinia showed progressive tumor growth when challenged with a tumorigenic dose of TC-1 tumor cells; in contrast, 80% of mice vaccinated with the chimeric Sig/E7/LAMP1 vaccinia remained tumor free 3 months after tumor injection. Furthermore, treatment with the Sig/E7/LAMP-1 vaccinia vaccine cured mice with small established TC-1 tumors, whereas the wild-type E7-vaccinia showed no effect on this established tumor burden. These findings point out the therapeutic limitations of recombinant vaccinia expressing unmodified tumor antigens. Further, they demonstrate that modifications that reroute a cytosolic tumor antigen to the endosomal/lysosomal compartment can profoundly improve the in vivo therapeutic potency of recombinant vaccines.