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Scand J Immunol. 2010 Feb;71(2):70-82. doi: 10.1111/j.1365-3083.2009.02355.x.

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.

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1
Department of Internal Medicine, University of Cincinnati Medical Center, Cincinnati, OH, USA. asaha@umn.edu

Abstract

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-gamma 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.

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