Skewing the T-cell repertoire by combined DNA vaccination, host conditioning, and adoptive transfer.
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.
Jorritsma
Annelies
A
Department of Immunology, the Netherlands Cancer Institute, Amsterdam, the Netherlands.
Bins
Adriaan D
AD
Schumacher
Ton N M
TN
Haanen
John B A G
JB
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
D010446:Peptide Fragments; D019444:Vaccines, DNA; D014758:Viral Core Proteins; C102366:nucleoprotein (366-374), influenza virus; D007371:Interferon-gamma