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.
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.
Slavin-Chiorini
Dale C
DC
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Catalfamo
Marta
M
Kudo-Saito
Chie
C
Hodge
James W
JW
Schlom
Jeffrey
J
Sabzevari
Helen
H
D000230:Adenocarcinoma / Q000276:immunology / Q000628:therapy*; D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D018122:B7-1 Antigen / Q000235:genetics; D015153:Blotting, Western; D000071178:CD48 Antigen; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000627:therapeutic use*; D002272:Carcinoembryonic Antigen / Q000276:immunology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology / Q000628:therapy*; D005434:Flow Cytometry; D019084:Fluorescent Antibody Technique, Indirect; D005587:Fowlpox virus / Q000235:genetics; D015870:Gene Expression / Q000502:physiology; D005822:Genetic Vectors; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D054353:Perforin; D016133:Polymerase Chain Reaction; D052899:Pore Forming Cytotoxic Proteins; D014614:Vaccines, Synthetic / Q000627:therapeutic use*
D015703:Antigens, CD; D018122:B7-1 Antigen; D000071178:CD48 Antigen; D019496:Cancer Vaccines; D002272:Carcinoembryonic Antigen; C000604066:Cd48 protein, mouse; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D014614:Vaccines, Synthetic; C479602:rF-TRICOM vaccine; D054353:Perforin; D018799:Intercellular Adhesion Molecule-1