Dendritic cells transduced with full-length wild-type p53 generate antitumor cytotoxic T lymphocytes from peripheral blood of cancer patients.
Accumulation of wild-type or mutant p53 protein occurs in approximately 50% of human malignancies. This overexpression may generate antigenic epitopes recognized by CTLs. Because normal cells have undetectable levels of p53, these CTLs are likely to be tumor specific. Here, for the first time, we test the hypothesis that full-length wild-type p53 protein can be used for generation of an immune response against tumor cells with p53 overexpression. T cells obtained from nine HLA-A2-positive cancer patients and three HLA-A2-positive healthy individuals were stimulated twice with dendritic cells (DCs) transduced with an adenovirus wild-type p53 (Ad-p53) construct. Significant cytotoxicity was detected against HLA-A2-positive tumor cells with accumulation of mutant or wild-type p53 but not against HLA-A2-positive tumor cells with normal (undetectable) levels of p53 or against HLA-A2-negative tumor cells. This response was specific and mediated by CD8+ CTLs. These CTLs recognized HLA-A2-positive tumor cells expressing normal levels of p53 protein after their transduction with Ad-p53 but not with control adenovirus. Stimulation of T cells with Ad-p53-transduced DCs resulted in generation of CTLs specific for p53-derived peptide. These data demonstrate that DCs transduced with the wild-type p53 gene were able to induce a specific antitumor immune response. This offers a new promising approach to immunotherapy of cancer.
Nikitina
E Y
EY
Cardinal Bemardin Cancer Center, Loyola University Medical Center, Maywood, Illinois 60153, USA.
Clark
J I
JI
Van Beynen
J
J
Chada
S
S
Virmani
A K
AK
Carbone
D P
DP
Gabrilovich
D I
DI
D000256:Adenoviridae / Q000235:genetics; D000328:Adult; D000368:Aged; D000818:Animals; D016827:CD8 Antigens / Q000276:immunology; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood*; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D015870:Gene Expression; D015789:HLA-A2 Antigen / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000097:blood*; D006801:Humans; D007124:Immunoenzyme Techniques; D007167:Immunotherapy; D008175:Lung Neoplasms / Q000097:blood*; D008259:Macroglobulins / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000276:immunology*
D016827:CD8 Antigens; D015789:HLA-A2 Antigen; D008259:Macroglobulins; D010446:Peptide Fragments; D016159:Tumor Suppressor Protein p53