Abstract
P53-based immunization is an attractive approach to cancer immunotherapy due to the accumulation of p53 protein in tumor, but not in normal cells. However, it was not known whether immune response against self-protein (p53) could be generated in vivo. Mouse dendritic cells (DCs) were transduced with adenoviral construct containing murine full-length wild-type p53 (Ad-p53). Repeated immunizations with these cells protected 60% of mice against challenge with MethA sarcoma cells bearing point mutations in p53 gene. Activation of DCs via ligation of CD40 significantly improved the results of immunization: all mice were protected against MethA sarcoma. The treatment of MethA tumor-bearing mice with activated Ad-p53-transduced DCs showed complete tumor rejection in four out of six mice. The specificity of antitumor immune response was confirmed by CTL assay. The analysis of phenotype and function of DCs demonstrated that the effect of CD40 ligation on these cells was enhanced by their infection with Ad-p53. The level of neutralizing anti-adenovirus antibody was moderately elevated in these mice. No signs of autoimmune reaction were evident during detailed pathological evaluation of treated mice. These data demonstrate that activated Ad-p53-infected DCs are able to break tolerance to this protein and can be used in immunotherapy of cancer.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Siliciano J. et al. DNA damage induces phosphorylation of the amino terminus of p53 Genes Dev 1997 11: 3471 3471
el-Deiry W.S. . WAF1, a potential mediator of p53 tumor suppression Cell 1993 75: 817 817
Harris C.C. . Structure and function of the p53 tumor suppressor gene: clues for rational cancer therapeutic strategies J Natl Cancer Inst 1996 88: 1442 1442
Hermeking H. et al. 14-3-3 sigma is a p53-regulated inhibitor of G2/M progression Mol Cell 1997 1: 3 3
Miyashita T., Reed J.C. . Tumor suppressor p53 is a direct transcriptional activator of the human bax gene Cell 1995 80: 293 293
Polyak K. et al. A model for p53-induced apoptosis Nature 1997 389: 300 300
Rogel A. et al. p53 cellular tumor antigen: analysis of mRNA levels in normal adult tissues, embryos, and tumors Mol Cell Biol 1985 5: 2851 2851
Prokocimer M., Rotter V. . Structure and function of p53 in normal cells and their aberrations in cancer cells: projection on the hematologic cell lineages Blood 1993 84: 2391 2391
Kaelin W.G. . The emerging p53 gene family J Natl Cancer Inst 1999 91: 594 594
Levine A.J., Momand J., Finlay C.A. . The p53 tumour suppressor gene Nature 1991 351: 453 453
Yanuck M. et al. Mutant p53 tumor suppressor protein is a target for peptide-induced CD8+ cytotoxic T-cells Cancer Res 1993 53: 3257 3257
Vierboom M.P.M. et al. Tumor eradication by wild-type p53-specific cytotoxic T lymphocytes J Exp Med 1997 186: 695 695
Theobald M. et al. Targeting p53 as a general tumor antigen Proc Natl Acad Sci USA 1995 92: 11993 11993
Mayordomo J.I. et al. Therapy of murine tumors with p53 wild-type and mutant sequence peptide-based vaccines J Exp Med 1996 183: 1357 1357
Gabrilovich D.I. et al. Dendritic cells in anti-tumor immune responses. II. Dendritic cells grown from bone marrow precursors, but not mature DC from tumor-bearing mice are effective antigen carriers in the therapy of established tumors Cell Immunol 1996 170: 111 111
Gabrilovich D.I., Cunningham H.T., Carbone D.P. . IL-12 and mutant p53 peptide-pulsed dendritic cells for the specific immunotherapy of cancer J Immunother 1997 19: 414 414
Nijman H.W. . p53, a potential target for tumor-directed T cells Immunol Lett 1994 40: 171 171
Mayordomo J.I. et al. Bone-marrow derived dendritic cells pulsed with synthetic tumour peptides elicit protective and therapeutic antitumour immunity Nature Med 1995 1: 1297 1297
Ropke M. et al. Spontaneous human squamous cell carcinomas are killed by a human cytotoxic T lymphocyte clone recognizing a wild-type p53-derived peptide Proc Natl Acad Sci USA 1996 93: 14704 14704
Chikamatsu K. et al. Generation of anti-p53 cytotoxic T lymphocytes from human peripheral blood using auologous dendritic cells Clin Cancer Res 1999 5: 1281 1281
Ryan M.H., Abrams S.I. . Characterization of CD8+ cytotoxic T lymphocyte/tumor cell interactions reflecting recognition of an endogenously expressed murine wild-type determinant Cancer Immunol Immunother 2001 49: 603 603
Ishida T. et al. Dendritic cells transduced with wild type p53 gene elicit potent antitumor immune responses Clin Exp Immunol 1999 117: 244 244
Nikitina E.Y. et al. Dendritic cells transduced with full-length wild-type p53 generate antitumor cytotoxic T lymphocytes from peripheral blood of cancer patients Clin Cancer Res 2001 7: 127 127
Theobald M. et al. Tolerance to p53 by A2.1-restricted cytotoxic T lymphocytes J Exp Med 1997 185: 833 833
Theobald M. et al. Tolerance to p53 by A2.1-restricted cytotoxic T lymphocytes
Vierboom MPM et al. P53: a target for T-cell-mediated immunotherapy. In: Kast WM (ed.). Peptide-based Cancer Vaccines. Landes Bioscience: 2000, pp 40–48 Vaccine 1998 16: 208 208
Avigan D. et al. Dendritic cells: development, function and potential use for cancer immunotherapy Blood Rev 1999 13: 51 51
Timmerman J.M., Levy R. . Dendritic cell vaccines for cancer immunotherapy Ann Rev Med 1999 50: 507 507
Chen C.-H., Wu T.C. . Experimental vaccine strategies for cancer immunotherapy J Biomed Sci 1998 5: 231 231
Chen P., Kovesdi I., Bruder J.T. . Effective repeat administration with adenovirus vectors to the muscle Gene Therapy 2000 7: 587 587
Brossart P. et al. Virus-mediated delivery of antigenic epitopes into dendritic cells as a means to induce CTL J Immunol 1997 158: 3270 3270
Fujita H. et al. Evidence that HLA class II-restricted human CD4+ T cells specific to p53 self peptides respond to p53 proteins of both wild and mutant forms Eur J Immunol 1998 28: 305 305
Labeur M.S. et al. Generation of tumor immunity by bone marrow-derived dendritic cells correlates with dendritic cell maturation stage J Immunol 1999 162: 168 168
Shurin M.R., Gabrilovich D.I. . Regulation of dendritic cell system by tumor Cancer Res Ther Cont 2001 11: 65 65
Almand B. et al. Increased production of immature myeloid cells in cancer patients. A mechanism of immunosuppression in cancer J Immunol 2001 166: 678 678
Aiba S., Tagami H. . Dendritic cell activation induced by various stimuli, eg exposure to microorganisms, their products, cytokines, and simple chemicals as well as adhesion to extracellular matrix J Dermatol Sci 1999 20: 1 1
Young J.W. . Dendritic cells: expansion and differentiation with hematopoietic growth factors Curr Opin Hematol 1999 6: 135 135
Ridge J.P., Di Rosa F., Matzinger P. . A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell Nature 1998 393: 474 474
Klein C., Bueler H., Mulligan R.C. . Comparative analysis of genetically modified dendritic cells and tumor cells as therapeutic cancer vaccines J Exp Med 2000 191: 1699 1699
Rea D. et al. Adenoviruses activate human dendritic cells without polarization toward a T-helper type 1-inducing subset J Virol 1999 73: 10245 10245
Acknowledgements
This work was supported by grant RPG 99-032 from American Cancer Society to DIG.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Nikitina, E., Chada, S., Muro-Cacho, C. et al. An effective immunization and cancer treatment with activated dendritic cells transduced with full-length wild-type p53. Gene Ther 9, 345–352 (2002). https://doi.org/10.1038/sj.gt.3301670
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.gt.3301670
Keywords
This article is cited by
-
Randomized-controlled phase II trial of salvage chemotherapy after immunization with a TP53-transfected dendritic cell-based vaccine (Ad.p53-DC) in patients with recurrent small cell lung cancer
Cancer Immunology, Immunotherapy (2019)
-
Specific cellular immune responses in mice immunized with DNA, adeno-associated virus and adenoviral vaccines of Epstein-Barr virus-LMP2 alone or in combination
Science China Life Sciences (2011)
-
Genetic changes in small cell lung carcinoma
Clinical and Translational Oncology (2008)
-
Combined modality immunotherapy and chemotherapy: a new perspective
Cancer Immunology, Immunotherapy (2008)
-
Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer
Nature Medicine (2007)