Combination of CTL‐associated Antigen‐4 Blockade and Depletion of CD25+ Regulatory T Cells Enhance Tumour Immunity of Dendritic Cell‐based Vaccine in a Mouse Model of Colon Cancer

Immune regulation has been shown to be involved in the progressive growth of some murine tumours. Interruption of immune regulatory pathways via CTL‐associated antigen‐4 (CTLA‐4) blockade or removal of CD4⁺ CD25⁺ regulatory T (Treg) cells appears to be a promising strategy for cancer immunotherapy. In this study, we tested the hypothesis that the combination of CTLA‐4 blockade and depletion of Treg cells would improve the potency of dendritic cell (DC)‐based vaccine in a clinically relevant mouse model, which is transgenic for both carcinoembryonic antigen (CEA) and HLA‐A2 for the treatment of colon carcinoma in a therapeutic setting. We found that administration of anti‐CD25 antibody prior to vaccination or systemic administration of anti‐CTLA‐4 antibody with the vaccine improved tumour‐free survival against CEA‐expressing tumours compared with mice immunized with DC‐based vaccine alone. However, the efficacy of the vaccine proved to be most effective when anti‐CTLA‐4 antibody was combined with Treg inhibition. This vaccination strategy dramatically improved the tumour‐free survival and allowed the development of long‐lasting immune responses. The combined vaccination strategy resulted in increased secretion of IFN‐γ and enhanced HLA‐A2‐restricted CEA‐specific CTL responses. Furthermore, coadministration of anti‐CD25 and anti‐CTLA‐4 antibodies along with the vaccine was effective against more advanced tumours. These results provide evidence that simultaneous blockade of T‐cell regulatory pathways is a promising approach for the induction of therapeutic antitumour immunity against CEA⁺ colon carcinoma.