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

• Published in: Scandinavian journal of immunology Vol. 71; no. 2; pp. 70 - 82
• Main Authors: Saha, Asim, Chatterjee, S.K
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01.02.2010; Blackwell Publishing Ltd
• Subjects: Animals; Antibodies, Antinuclear - blood; Antibodies, Antinuclear - immunology; Antigens, CD - immunology; Cancer Vaccines - immunology; Carcinoembryonic Antigen - immunology; Cell Separation; Colonic Neoplasms - immunology; Colonic Neoplasms - therapy; CTLA-4 Antigen; Dendritic Cells - transplantation; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; HLA-A2 Antigen - immunology; Immunotherapy - methods; Interleukin-2 Receptor alpha Subunit - antagonists & inhibitors; Interleukin-2 Receptor alpha Subunit - immunology; Lymphocyte Depletion; Mice; Mice, Transgenic; T-Lymphocyte Subsets - immunology; T-Lymphocytes, Regulatory - immunology
• ISSN: 0300-9475; 1365-3083
• DOI: 10.1111/j.1365-3083.2009.02355.x

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.