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. Int J Cancer 2007 Oct 01;121(7):1520-8
Date
06/15/2007Pubmed ID
17565748DOI
10.1002/ijc.22873Scopus ID
2-s2.0-34548284487 (requires institutional sign-in at Scopus site) 41 CitationsAbstract
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.
Author List
Karan D, Krieg AM, Lubaroff DMMESH terms used to index this publication - Major topics in bold
AdenoviridaeAnimals
CD8-Positive T-Lymphocytes
Cancer Vaccines
Cell Line, Tumor
Cell Proliferation
Cell Survival
Enzyme-Linked Immunosorbent Assay
Interferon-gamma
Male
Mice
Mice, Inbred C57BL
Neoplasms, Experimental
Oligodeoxyribonucleotides
Ovalbumin
T-Lymphocytes, Cytotoxic
Toll-Like Receptor 9
Vaccination
