title: Paradoxical enhancement of CD8 T cell-dependent anti-tumor protection despite reduced CD8 T cell responses with addition of a TLR9 agonist to a tumor vaccine.
abstract: Generation of antigen-specific CD8+ T cell responses is considered optimal for an effective immunotherapy against cancer. In this study, we provide a proof of principle that in vitro observed diminished CD8+ T cell response provided a strong in vivo tumor protection. Immunization with an adenovirus vaccine containing ovalbumin (OVA) gene (Ad5-OVA) strongly induces antigen-specific CD8+ T cell responses measured in vitro using various immunological assays. However, in an attempt to augment the antigenic CD8+ T cell response, coinjection of a TLR9 agonist CpG ODN with the viral vaccine unexpectedly reduced the CD8+ T cell responses measured in vitro but provided a remarkably enhanced tumor protection compared to the CD8+ T cell response generated by Ad5-OVA vaccine alone. Interestingly, despite reduced ex vivo/in vitro CD8+ T cell responses following Ad5-OVA+CpG immunization, immunodepletion studies revealed that the augmented anti-tumor immunity was primarily dependent on CD8+ T cells. The magnitude and effector function of anti-OVA CD8+ T cells remain low following primary and secondary antigenic challenge, presenting a dichotomy between in vitro CD8 T cell responses and in vivo anti-tumor immunity. To examine the impact of CpG ODN, we observed that presence of CpG suppresses the CD8+ T cell proliferation both in vitro and in vivo. These data demonstrate that coadministration of adenovirus vaccine with a TLR9 agonist can generate potentially effective tumor-reactive CD8+ T cells in vivo. In addition, the results indicate that widely used standard immune parameters may not predict the vaccine efficacy containing a TLR9 agonist as adjuvant.
authors.affiliation: VA Medical Center, Iowa City, IA, USA.
authors.forename: Dev
authors.initials: D
authors.lastname: Karan
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Krieg
authors.forename: David M
authors.initials: DM
authors.lastname: Lubaroff
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D004797:Enzyme-Linked Immunosorbent Assay; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage*; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000819:agonists; D014611:Vaccination / Q000379:methods
chemical_list: C408982:CPG-oligonucleotide; D019496:Cancer Vaccines; D009838:Oligodeoxyribonucleotides; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D007371:Interferon-gamma; D010047:Ovalbumin