Establishment of animal models to analyze the kinetics and distribution of human tumor antigen-specific CD8 T cells |
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| Authors: | Daisuke Muraoka Hiroyoshi Nishikawa Takuro Noguchi Linan Wang Naozumi Harada Eiichi Sato Immanuel Luescher Eiichi Nakayama Takuma Kato Hiroshi Shiku |
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| Institution: | 1. Departments of Cancer Vaccine, Mie University Graduate School of Medicine, Mie 514-8507, Japan;2. Departments of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Mie 514-8507, Japan;3. Departments of Cellular and Molecular Immunology, Mie University Graduate School of Medicine, Mie 514-8507, Japan;4. Immunofrontier, Inc., Tokyo, 143-0023, Japan;5. Experimental Immunology, Immunology Frontier Research Center, Osaka University, Osaka, 565-0871, Japan;6. Ludwig Institute for Cancer Research, New York Branch, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, United States;g Department of Anatomic Pathology, Tokyo Medical University, Tokyo, 160-8402, Japan;h Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, 1066, Switzerland;i Faculty of Health and Welfare, Kawasaki University of Medical Welfare, Okayama, 701-0193, Japan |
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| Abstract: | Many patients develop tumor antigen-specific T cell responses detectable in peripheral blood mononuclear cells (PBMCs) following cancer vaccine. However, measurable tumor regression is observed in a limited number of patients receiving cancer vaccines. There is a need to re-evaluate systemically the immune responses induced by cancer vaccines. Here, we established animal models targeting two human cancer/testis antigens, NY-ESO-1 and MAGE-A4. Cytotoxic T lymphocyte (CTL) epitopes of these antigens were investigated by immunizing BALB/c mice with plasmids encoding the entire sequences of NY-ESO-1 or MAGE-A4. CD8+ T cells specific for NY-ESO-1 or MAGE-A4 were able to be detected by ELISPOT assays using antigen presenting cells pulsed with overlapping peptides covering the whole protein, indicating the high immunogenicity of these antigens in mice. Truncation of these peptides revealed that NY-ESO-1-specific CD8+ T cells recognized Dd-restricted 8mer peptides, NY-ESO-181-88. MAGE-A4-specific CD8+ T cells recognized Dd-restricted 9mer peptides, MAGE-A4265-273. MHC/peptide tetramers allowed us to analyze the kinetics and distribution of the antigen-specific immune responses, and we found that stronger antigen-specific CD8+ T cell responses were required for more effective anti-tumor activity. Taken together, these animal models are valuable for evaluation of immune responses and optimization of the efficacy of cancer vaccines. |
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| Keywords: | APC antigen presenting cells CTL cytotoxic T lymphocyte dLN draining lymph node ELISPOT assay enzyme-linked immunospot assay IFN interferon mAb monoclonal antibody PBMC peripheral blood mononuclear cells |
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