Anti-tumor effects of DNA vaccine targeting human fibroblast activation protein alpha by producing specific immune responses and altering tumor microenvironment in the 4T1 murine breast cancer model

摘要

Fibroblast activation protein alpha (FAP alpha) is a tumor stromal antigen overexpressed by cancer-associated fibroblasts (CAFs). CAFs are genetically more stable compared with the tumor cells and immunosuppressive components of the tumor microenvironment, rendering them excellent targets for cancer immunotherapy. DNA vaccines are widely applied due to their safety. To specifically destroy CAFs, we constructed and examined the immunogenicity and anti-tumor immune mechanism of a DNA vaccine expressing human FAP alpha. This vaccine successfully reduced 4T1 tumor growth through producing FAP alpha-specific cytotoxic T lymphocyte responses which could kill CAFs, and the decrease in FAP alpha-expressing CAFs resulted in markedly attenuated expression of collagen I and other stromal factors that benefit the tumor progression. Based on these results, a DNA vaccine targeting human FAP alpha may be an attractive and effective cancer immunotherapy strategy.