TH2 Antibody Response to Autocatalytic Loop of Membrane Serine Protease, PRSS14 can Reduce Primary Tumor Growth and Abrogate Metastasis

초록

PRSS14/Epithin is a type II transmembrane serine protease that plays important roles in cancer progression and metastasis. It is involved in angiogenesis, epithelial to mesenchymal transition, and transendothelial migration. We established two mouse orthotopic cancer models using breast cancer cell lines, 4T1 and E0771, and their syngenic mouse strains, Balb/c (TH2 type) and C57BL/6 (TH1 type), respectively. Orthotopic injection of PRSS14/Epithin knockdown breast cancer cell lines in 7th mammary fat pad significantly reduced lung metastasis. Immunizing mice with structure specific peptide antigens designed by informatics and computer modeling produced sequence specific antibodies and reduced lung metastasis in both animals, indicating conjugated peptides can be efficiently used as preventive metastasis vaccine. An engineered autocatalytic loop peptide similar to its original structure in intact protein showed effects of a metastasis vaccine in the two mouse models. Immunized animals produced different antibody isotypes. TH1 and TH2 types with CFA adjuvant, dominant TH2 type with Alum and MF59 adjuvant, and dominant TH1 type with CpG adjuvant. Metavaccine effects show strong correlation with TH2 isotype antibodies. While TH2 type adjuvant enhance metavaccine efficacy without any hazardous side effects, CFA adjuvant showed strong adverse effect in the prevention of metastasis that it also reduced survival of host animal during 6 months watch, indicating TH1 immune response can be dangerous. Therefore, we concluded that TH2 type antibody is efficient and safe approach for a preventive metastasis vaccine.