A novel DNA vaccine based on ubiquitin-proteasome pathway targeting 'self'-antigens expressed in melanoma/melanocyte.
Cancer vaccine that targets 'self'-antigens expressed at high levels in tumor cells is a potentially useful immunotherapy, but immunological tolerance often defeats this strategy. Here, we describe the use of a naked DNA vaccine encoding a self tumor antigen, tyrosinase-related protein 2, to whose N-terminus ubiquitin is fused in a 'nonremovable' fashion. Unlike conventional DNA vaccines, this vaccine broke the tolerance and induced protective immunity to melanoma in C57BL/6 mice, as evaluated by tumor growth, survival rate and lung metastasis. The protective immunity was cancelled in the proteasome activator PA28alpha/beta knockout mice. Moreover, this vaccination exhibited therapeutic effects on melanoma implanted before vaccination. Our findings provide evidence for the first time that naked DNA vaccines encoding a ubiquitin-fused self-antigen preferentially induce the main effector CD8+ T cells through efficient proteolysis mediated by the ubiquitin-proteasome pathway, and lead the way to strategies aimed at targeting tissue differentiation antigens expressed by tumors.
Zhang
M
M
Department of Microbiology and Immunology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Japan.
Obata
C
C
Hisaeda
H
H
Ishii
K
K
Murata
S
S
Chiba
T
T
Tanaka
K
K
Li
Y
Y
Furue
M
M
Chou
B
B
Imai
T
T
Duan
X
X
Himeno
K
K
D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage*; D003601:Cytotoxicity Tests, Immunologic; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D007371:Interferon-gamma / Q000032:analysis; D008544:Melanocytes / Q000276:immunology; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000276:immunology / Q000628:therapy*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D025801:Ubiquitin / Q000378:metabolism; D019444:Vaccines, DNA / Q000008:administration & dosage*
D001324:Autoantigens; D019496:Cancer Vaccines; D025801:Ubiquitin; D019444:Vaccines, DNA; D007371:Interferon-gamma; D046988:Proteasome Endopeptidase Complex