title: Comparison of vaccine-induced effector CD8 T cell responses directed against self- and non-self-tumor antigens: implications for cancer immunotherapy.
abstract: It is generally accepted that CD8 T cells play a major role in tumor control, yet vaccination aimed at eliciting potent CD8 T cell responses are rarely efficient in clinical trials. To try and understand why this is so, we have generated potent adenoviral vectors encoding the endogenous tumor Ags (TA) tyrosinase-related protein-2 (TRP-2) and glycoprotein 100 (GP100) tethered to the invariant chain (Ii). Using these vectors, we sought to characterize the self-TA-specific CD8 T cell response and compare it to that induced against non-self-Ags expressed from a similar vector platform. Prophylactic vaccination with adenoviral vectors expressing either TRP-2 (Ad-Ii-TRP-2) or GP100 (Ad-Ii-GP100) had little or no effect on the growth of s.c. B16 melanomas, and only Ad-Ii-TRP-2 was able to induce a marginal reduction of B16 lung metastasis. In contrast, vaccination with a similar vector construct expressing a foreign (viral) TA induced efficient tumor control. Analyzing the self-TA-specific CD8 T cells, we observed that these could be activated to produce IFN-γ and TNF-α. In addition, surface expression of phenotypic markers and inhibitory receptors, as well as in vivo cytotoxicity and degranulation capacity matched that of non-self-Ag-specific CD8 T cells. However, the CD8 T cells specific for self-TAs had a lower functional avidity, and this impacted on their in vivo performance. On the basis of these results and a low expression of the targeted TA epitopes on the tumor cells, we suggest that low avidity of the self-TA-specific CD8 T cells may represent a major obstacle for efficient immunotherapy of cancer.
authors.affiliation: Department of International Health, Immunology and Microbiology, University of Copenhagen, DK-2200 Copenhagen North, Denmark.
authors.forename: Sara R
authors.initials: SR
authors.lastname: Pedersen
authors.forename: Maria R
authors.initials: MR
authors.lastname: Sørensen
authors.forename: Søren
authors.initials: S
authors.lastname: Buus
authors.forename: Jan P
authors.initials: JP
authors.lastname: Christensen
authors.forename: Allan R
authors.initials: AR
authors.lastname: Thomsen
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology*; D015550:Cell Degranulation / Q000276:immunology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D005260:Female; D005822:Genetic Vectors / Q000235:genetics; D007167:Immunotherapy; D007371:Interferon-gamma / Q000096:biosynthesis; D019746:Intramolecular Oxidoreductases / Q000276:immunology / Q000378:metabolism; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy; D008544:Melanocytes / Q000276:immunology; D051379:Mice; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy; D010641:Phenotype; D011485:Protein Binding / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014161:Transduction, Genetic; D058951:gp100 Melanoma Antigen / Q000276:immunology / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D001324:Autoantigens; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D011948:Receptors, Antigen, T-Cell; D058951:gp100 Melanoma Antigen; D007371:Interferon-gamma; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase