title: Skewing the T-cell repertoire by combined DNA vaccination, host conditioning, and adoptive transfer.
abstract: Approaches for T-cell-based immunotherapy that have shown substantial effects in clinical trials are generally based on the adoptive transfer of high numbers of antigen-specific cells, and the success of these approaches is thought to rely on the high magnitude of the tumor-specific T-cell responses that are induced. In this study, we aimed to develop strategies that also yield a T-cell repertoire that is highly skewed toward tumor recognition but do not rely on ex vivo generation of tumor-specific T cells. To this end, the tumor-specific T-cell repertoire was first expanded by DNA vaccination and then infused into irradiated recipients. Subsequent vaccination of the recipient mice with the same antigen resulted in peak CD8(+) T-cell responses of approximately 50%. These high T-cell responses required the presence of antigen-experienced tumor-specific T cells within the graft because only mice that received cells of previously vaccinated donor mice developed effective responses. Tumor-bearing mice treated with this combined therapy showed a significant delay in tumor outgrowth, compared with mice treated by irradiation or vaccination alone. Furthermore, this antitumor effect was accompanied by an increased accumulation of activated and antigen-specific T cells within the tumor. In summary, the combination of DNA vaccination with host conditioning and adoptive transfer generates a marked, but transient, skewing of the T-cell repertoire toward tumor recognition. This strategy does not require ex vivo expansion of cells to generate effective antitumor immunity and may therefore easily be translated to clinical application.
authors.affiliation: Department of Immunology, the Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Annelies
authors.initials: A
authors.lastname: Jorritsma
authors.forename: Adriaan D
authors.initials: AD
authors.lastname: Bins
authors.forename: Ton N M
authors.initials: TN
authors.lastname: Schumacher
authors.forename: John B A G
authors.initials: JB
authors.lastname: Haanen
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003131:Combined Modality Therapy; D005260:Female; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D019444:Vaccines, DNA / Q000276:immunology* / Q000494:pharmacology; D014758:Viral Core Proteins / Q000235:genetics / Q000276:immunology
chemical_list: D010446:Peptide Fragments; D019444:Vaccines, DNA; D014758:Viral Core Proteins; C102366:nucleoprotein (366-374), influenza virus; D007371:Interferon-gamma