Immune checkpoint Ab enhances the antigen-specific anti-tumor effects by modulating both dendritic cells and regulatory T lymphocytes

摘要

We determined the anti-tumor effects and possible mechanisms of an antigen-specific DNA vaccine combined with PD-1 or CTLA-4 blockade. Using the HPV16 E6/E7(+) syngeneic mouse tumor model, we investigated whether anti-CTLA-4 antibody (Ab) or anti-PD-1 Ab increases the antigen-specific anti-tumor effects and immune response induced by CTGF/E7 chimeric DNA vaccine and the possible mechanisms. Anti-PD-1 Ab or anti-CTLA-4 Ab combined with E7-specific DNA vaccine generated more potent antigen-specific immunity, including anti-E7 Abs and the number and cytotoxic activity of E7-specific cytotoxic CD8(+) T lymphocytes, and anti-tumor effects than E7-specific DNA vaccine alone. In addition, the number of systemic and intratumoral Tregs was lower with the anti-PD-1 or anti-CTLA-4 Ab and E7-specific DNA vaccine. Furthermore, anti-PD-1 and anti-CTLA-4 Abs could enhance the maturation and abilities of intratumoral DCs to activate E7-specific cytotoxic CD8(+) T cells. Immune checkpoint blockade overcomes the immunosuppressive status of the tumor-micro environment to enhance the antigen-specific immunity and anti-tumor effects generated by an antigen-specific DNA vaccine. Antigen-specific immunotherapy combined with immune checkpoint blockade can be a novel strategy in clinical cancer therapy.