Lentivector immunization stimulates potent CD8 T cell responses against melanoma self-antigen tyrosinase-related protein 1 and generates antitumor immunity in mice.
Recombinant lentivector immunization has been demonstrated to induce potent CD8 T cell responses in vivo. In this study, we investigated whether lentivector delivering a self/tumor Ag, tyrosinase related protein 1 (TRP1), could stimulate effective antitumor T cell responses. We found that immunization with lentivector expressing mutated TRP1 Ag elicited potent CD8 T cell responses against multiple TRP1 epitopes. Importantly, the activated CD8 T cells effectively recognize wild-type TRP1 epitopes. At peak times, as many as 10% of CD8 T cells were effector cells against TRP1 Ag. These cells killed wild-type TRP1 peptide-pulsed target cells in vivo and produced IFN-gamma after ex vivo stimulation. The CD8 T cell responses were long-lasting (3-4 wk). Immunized mice were protected from B16 tumor cell challenge. In a therapeutic setting, lentivector immunization induced potent CD8 T cell responses in tumor bearing mice. The number of infiltrating T cells and the ratio of CD8/CD4 were dramatically increased in the tumors of immunized mice. The tumor-infiltrating CD8 T cells were functional and produced IFN-gamma. The potent CD8 T cell responses stimulated by lentivector immunization eliminated small 3-day s.c. B16 tumors and strongly inhibited the growth of more established 5-day tumors. These studies demonstrate that genetic immunization with lentivector expressing mutated self/tumor Ag can generate potent CD8 T cell immune responses and antitumor immunity that prevent and inhibit B16 tumor growth, suggesting that lentivector immunization has the potential for tumor immunotherapy and immune prevention.
Immunology/Immunotherapy Program, Medical College of Georgia Cancer Center, Medical College of Georgia, Augusta, GA 30912, USA.
Yanjun
Y
Liu
Yibing
Y
Peng
Michael
M
Mi
Jose
J
Guevara-Patino
David H
DH
Munn
Ning
N
Fu
Yukai
Y
He
D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D001324:Autoantigens / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005822:Genetic Vectors / Q000276:immunology*; D016086:Lentivirus / Q000235:genetics / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000628:therapy; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D009154:Mutation; D010088:Oxidoreductases / Q000276:immunology*
D000951:Antigens, Neoplasm; D001324:Autoantigens; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D008562:Membrane Glycoproteins; D010088:Oxidoreductases; C079621:Tyrp1 protein, mouse