In vivo augmentation of tumor-specific CTL responses by class I/peptide antigen complexes on microspheres (large multivalent immunogen).
Tumor membrane Ag immobilized on cell size microspheres (large multivalent immunogen (LMI)) was previously shown to augment tumor-specific CTL activity and reduce tumor growth, and a clinical trial examining this approach is in progress. In the current study, LMI treatment has been examined using adoptive transfer of TCR-transgenic CD8 T cells to visualize Ag-specific cells during the response. OT-I T cells specific for H-2K(b)/OVA(257-264) were transferred into mice that were then challenged with LMI made by immobilizing H-2K(b)/OVA(257-264) on microspheres (K(b)/OVA(257-264)-LMI) alone, or along with i.p. challenge with OVA-expressing E.G7 tumor. K(b)/OVA(257-264)-LMI caused significant reduction of tumor growth when administered to E.G7-bearing mice. When administered alone, the K(b)/OVA(257-264)-LMI caused only weak clonal expansion of OT-I cells in the spleen and lymph nodes, although most of the OT-I cells up-regulated expression of CD44 and VLA-4. In contrast, K(b)/OVA(257-264)-LMI administration to E.G7-bearing mice stimulated no detectable expansion of OT-I cells in the spleen and lymph nodes but caused a rapid increase in the number of OT-I cells in the peritoneal cavity, the site of the growing tumor. These results demonstrate the potential for using class I/tumor peptide complexes for immunotherapy. In addition, they suggest a model for the mechanism of CTL augmentation in which recognition of the LMI Ag results in altered trafficking of the tumor-specific CD8 T cells so that they reach the site of a growing tumor more rapidly and in greater numbers, where they may further expand and acquire effector function.
Goldberg
Jodi
J
Center for Immunology, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
Shrikant
Protul
P
Mescher
Matthew F
MF
D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000502:physiology*; D019264:Adoptive Transfer; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D004527:Egg Proteins / Q000008:administration & dosage / Q000276:immunology*; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D006183:H-2 Antigens / Q000008:administration & dosage / Q000276:immunology / Q000502:physiology*; D016056:Immunodominant Epitopes / Q000502:physiology; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008213:Lymphocyte Activation / Q000276:immunology*; D046911:Macromolecular Substances; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008863:Microspheres; D009368:Neoplasm Transplantation; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology*; D010446:Peptide Fragments; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000637:transplantation*; D013945:Thymoma / Q000276:immunology / Q000517:prevention & control; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; D004527:Egg Proteins; D006131:Growth Inhibitors; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D016056:Immunodominant Epitopes; D046911:Macromolecular Substances; C110366:OVA-8; D010446:Peptide Fragments; D010047:Ovalbumin