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 ∼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 hypoth...

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Bibliographic Details
Published in:Clinical cancer research 2001-01, Vol.7 (1), p.127-135
Main Authors: NIKITINA, Ekaterina Yu, CLARK, Joseph I, VAN BEYNEN, James, CHADA, Sunil, VIRMANI, Arvind K, CARBONE, David P, GABRILOVICH, Dmitry I
Format: Article
Language:English
Subjects:
Adenoviridae - genetics
Adult
Aged
Animals
Antineoplastic agents
Biological and medical sciences
Carcinoma, Non-Small-Cell Lung - blood
CD8 Antigens - immunology
Dendritic Cells - immunology
Female
Gene Expression
Head and Neck Neoplasms - blood
HLA-A2 Antigen - metabolism
Humans
Immunoenzyme Techniques
Immunotherapy
Lung Neoplasms - blood
Macroglobulins - immunology
Macroglobulins - metabolism
Male
Medical sciences
Mice
Middle Aged
Peptide Fragments - immunology
Peptide Fragments - metabolism
Pharmacology. Drug treatments
T-Lymphocytes, Cytotoxic - immunology
Tumor Cells, Cultured - drug effects
Tumor Suppressor Protein p53 - biosynthesis
Tumor Suppressor Protein p53 - immunology
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Summary:Accumulation of wild-type or mutant p53 protein occurs in ∼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.
ISSN:1078-0432
1557-3265