1. Amplification of the lytic potential of effector/memory CD8+ cells by vector-based enhancement of ICAM-1 (CD54) in target cells: implications for intratumoral vaccine therapy.
- Author
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Slavin-Chiorini DC, Catalfamo M, Kudo-Saito C, Hodge JW, Schlom J, and Sabzevari H
- Subjects
- Adenocarcinoma immunology, Animals, Antigens, CD genetics, B7-1 Antigen genetics, Blotting, Western, CD48 Antigen, Carcinoembryonic Antigen immunology, Cell Line, Tumor, Colonic Neoplasms immunology, Flow Cytometry, Fluorescent Antibody Technique, Indirect, Fowlpox virus genetics, Gene Expression physiology, Intercellular Adhesion Molecule-1 metabolism, Membrane Glycoproteins metabolism, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neoplasm Transplantation, Perforin, Polymerase Chain Reaction, Pore Forming Cytotoxic Proteins, Adenocarcinoma therapy, CD8-Positive T-Lymphocytes immunology, Cancer Vaccines therapeutic use, Colonic Neoplasms therapy, Genetic Vectors, Intercellular Adhesion Molecule-1 genetics, Vaccines, Synthetic therapeutic use
- Abstract
We demonstrated that enhanced expression of the costimulatory molecules CD80, CD54 and CD48 (designated rF-TRICOM) on target cells, as delivered via a recombinant fowlpox vector, results in an increased state of stimulation of CD8+ T cells, and consequent increased lysis of target cells. CTL studies in conjunction with antibody-blocking studies demonstrated that the enhanced effector activity of these CD8+ T cells is mediated mainly through CD54. Intracellular staining of CD8+ cells that interact with target cells infected with rF-TRICOM showed that they contain higher amounts of perforin and have a higher level of perforin message. Enhanced expression of costimulatory molecules (specifically CD54) on target cells using rF-TRICOM vectors also leads to the formation of stable conjugates/synapses between targets and T cells. The interaction of T cells with target cells that overexpress costimulatory molecules upon infection with rF-TRICOM leads to enhanced signaling through Lck, ZAP70, and STAT-1 in CD8+ T cells and heightened lytic activity of CD8+ cells through the formation of a greater number of immunological synapses. This, in turn, leads to enhanced signaling in T cells. Finally, studies were conducted in mice in which CEA is a self-antigen in an attempt to understand the potential clinical relevancy of intratumoral vaccine therapy. Mice were transplanted subcutaneously with CEA expressing tumors. Intratumoral (i.t.) vaccination was administered 8 days post tumor transplant. Mice vaccinated i.t. with rF-TRICOM demonstrated significantly reduced tumor growth and 40% of the mice had complete tumor regression. The antitumor effects were further improved by the addition of tumor antigen (CEA) in the vaccination by utilizing rF-CEA/TRICOM, with 80% of the mice experiencing complete tumor regression. These studies thus support the concept of intratumoral vaccination employing vectors expressing costimulatory molecules.
- Published
- 2004
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