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Tumor eradication by wild-type p53-specific cytotoxic T lymphocytes.

Vierboom MP, Nijman HW, Offringa R, van der Voort EI, van Hall T, van den Broek L, Fleuren GJ, Kenemans P, Kast WM, Melief CJ - J. Exp. Med. (1997)

Bottom Line: The tumor suppressor protein p53 is overexpressed in close to 50% of all human malignancies.The p53 protein is therefore an attractive target for immunotherapy.Importantly, this occurred in the absence of any demonstrable damage to normal tissue.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunohematology and Blood Bank, University Hospital Leiden, 2300 RC Leiden, the Netherlands.

ABSTRACT
The tumor suppressor protein p53 is overexpressed in close to 50% of all human malignancies. The p53 protein is therefore an attractive target for immunotherapy. Cytotoxic T lymphocytes (CTLs) recognizing a murine wild-type p53 peptide, presented by the major histocompatibility complex class I molecule H-2Kb, were generated by immunizing p53 gene deficient (p53 -/-) C57BL/6 mice with syngeneic p53-overexpressing tumor cells. Adoptive transfer of these CTLs into tumor-bearing p53 +/+ nude mice caused complete and permanent tumor eradication. Importantly, this occurred in the absence of any demonstrable damage to normal tissue. When transferred into p53 +/+ immunocompetent C57BL/6 mice, the CTLs persisted for weeks in the absence of immunopathology and were capable of preventing tumor outgrowth. Wild-type p53-specific CTLs can apparently discriminate between p53-overexpressing tumor cells and normal tissue, indicating that widely expressed autologous molecules such as p53 can serve as a target for CTL-mediated immunotherapy of tumors.

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Lytic ability of wt p53-specific CTL clone 1H11 on a panel  of normal and tumor cells. (A) A panel of Eu3+-labeled C57BL/6-derived  cell lines were tested for lysis by p53-specific CTL clone 1H11 in a cytotoxicity assay. The following targets were tested for recognition: MEC  (filled circles); C3: HPV16 + EJras (open triangles); 5A (open diamonds) and  5D (filled diamonds): p53 + N-ras; 6J3: p53 + fos (open squares); 4J: p53 +  H-ras (filled squares); and Con A–stimulated spleen cells (filled triangles).  The p53 −/− Koko cell line (open circles) was taken along as the negative  control. (B) Lack of recognition of freshly isolated thymocytes (open triangles) by the p53-specific CTL clone 1H11 in a 51Cr–cytotoxicicty assay  (29). Thymocytes are recognized by the p53-specific CTL clone 1H11  when pulsed with the wt p53 peptide AIYKKSQHM (filled triangles). p53  −/− Koko cells, with (filled circles) and without (open circles) this peptide,  were taken along as a positive control for recognition of the peptide.
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Figure 3: Lytic ability of wt p53-specific CTL clone 1H11 on a panel of normal and tumor cells. (A) A panel of Eu3+-labeled C57BL/6-derived cell lines were tested for lysis by p53-specific CTL clone 1H11 in a cytotoxicity assay. The following targets were tested for recognition: MEC (filled circles); C3: HPV16 + EJras (open triangles); 5A (open diamonds) and 5D (filled diamonds): p53 + N-ras; 6J3: p53 + fos (open squares); 4J: p53 + H-ras (filled squares); and Con A–stimulated spleen cells (filled triangles). The p53 −/− Koko cell line (open circles) was taken along as the negative control. (B) Lack of recognition of freshly isolated thymocytes (open triangles) by the p53-specific CTL clone 1H11 in a 51Cr–cytotoxicicty assay (29). Thymocytes are recognized by the p53-specific CTL clone 1H11 when pulsed with the wt p53 peptide AIYKKSQHM (filled triangles). p53 −/− Koko cells, with (filled circles) and without (open circles) this peptide, were taken along as a positive control for recognition of the peptide.

Mentions: To establish whether this epitope is commonly expressed, mutant p53-transformed cells and other tumor cells, with no known p53 overexpression, were tested for recognition. The lysis of HPV16 transformed tumor cell line C3 (36; Fig. 3 A) and the thymoma EL-4 (data not shown) by CTL clone 1H11 was comparable to the lysis of other p53-overexpressing lines 4J, 5A, 5D, and 6J3 (Fig. 3 A). Strikingly, nontransformed B6MEC and Con A–stimulated T cell blasts were efficiently recognized by CTL clone 1H11 (Fig. 3 A), demonstrating the potential cross-reacting ability of these p53-specific CTLs to nonmalignant cells. On the other hand, freshly isolated thymocytes (Fig. 3 B) and freshly isolated spleen cells (data not shown) are not lysed by these CTLs.


Tumor eradication by wild-type p53-specific cytotoxic T lymphocytes.

Vierboom MP, Nijman HW, Offringa R, van der Voort EI, van Hall T, van den Broek L, Fleuren GJ, Kenemans P, Kast WM, Melief CJ - J. Exp. Med. (1997)

Lytic ability of wt p53-specific CTL clone 1H11 on a panel  of normal and tumor cells. (A) A panel of Eu3+-labeled C57BL/6-derived  cell lines were tested for lysis by p53-specific CTL clone 1H11 in a cytotoxicity assay. The following targets were tested for recognition: MEC  (filled circles); C3: HPV16 + EJras (open triangles); 5A (open diamonds) and  5D (filled diamonds): p53 + N-ras; 6J3: p53 + fos (open squares); 4J: p53 +  H-ras (filled squares); and Con A–stimulated spleen cells (filled triangles).  The p53 −/− Koko cell line (open circles) was taken along as the negative  control. (B) Lack of recognition of freshly isolated thymocytes (open triangles) by the p53-specific CTL clone 1H11 in a 51Cr–cytotoxicicty assay  (29). Thymocytes are recognized by the p53-specific CTL clone 1H11  when pulsed with the wt p53 peptide AIYKKSQHM (filled triangles). p53  −/− Koko cells, with (filled circles) and without (open circles) this peptide,  were taken along as a positive control for recognition of the peptide.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2199025&req=5

Figure 3: Lytic ability of wt p53-specific CTL clone 1H11 on a panel of normal and tumor cells. (A) A panel of Eu3+-labeled C57BL/6-derived cell lines were tested for lysis by p53-specific CTL clone 1H11 in a cytotoxicity assay. The following targets were tested for recognition: MEC (filled circles); C3: HPV16 + EJras (open triangles); 5A (open diamonds) and 5D (filled diamonds): p53 + N-ras; 6J3: p53 + fos (open squares); 4J: p53 + H-ras (filled squares); and Con A–stimulated spleen cells (filled triangles). The p53 −/− Koko cell line (open circles) was taken along as the negative control. (B) Lack of recognition of freshly isolated thymocytes (open triangles) by the p53-specific CTL clone 1H11 in a 51Cr–cytotoxicicty assay (29). Thymocytes are recognized by the p53-specific CTL clone 1H11 when pulsed with the wt p53 peptide AIYKKSQHM (filled triangles). p53 −/− Koko cells, with (filled circles) and without (open circles) this peptide, were taken along as a positive control for recognition of the peptide.
Mentions: To establish whether this epitope is commonly expressed, mutant p53-transformed cells and other tumor cells, with no known p53 overexpression, were tested for recognition. The lysis of HPV16 transformed tumor cell line C3 (36; Fig. 3 A) and the thymoma EL-4 (data not shown) by CTL clone 1H11 was comparable to the lysis of other p53-overexpressing lines 4J, 5A, 5D, and 6J3 (Fig. 3 A). Strikingly, nontransformed B6MEC and Con A–stimulated T cell blasts were efficiently recognized by CTL clone 1H11 (Fig. 3 A), demonstrating the potential cross-reacting ability of these p53-specific CTLs to nonmalignant cells. On the other hand, freshly isolated thymocytes (Fig. 3 B) and freshly isolated spleen cells (data not shown) are not lysed by these CTLs.

Bottom Line: The tumor suppressor protein p53 is overexpressed in close to 50% of all human malignancies.The p53 protein is therefore an attractive target for immunotherapy.Importantly, this occurred in the absence of any demonstrable damage to normal tissue.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunohematology and Blood Bank, University Hospital Leiden, 2300 RC Leiden, the Netherlands.

ABSTRACT
The tumor suppressor protein p53 is overexpressed in close to 50% of all human malignancies. The p53 protein is therefore an attractive target for immunotherapy. Cytotoxic T lymphocytes (CTLs) recognizing a murine wild-type p53 peptide, presented by the major histocompatibility complex class I molecule H-2Kb, were generated by immunizing p53 gene deficient (p53 -/-) C57BL/6 mice with syngeneic p53-overexpressing tumor cells. Adoptive transfer of these CTLs into tumor-bearing p53 +/+ nude mice caused complete and permanent tumor eradication. Importantly, this occurred in the absence of any demonstrable damage to normal tissue. When transferred into p53 +/+ immunocompetent C57BL/6 mice, the CTLs persisted for weeks in the absence of immunopathology and were capable of preventing tumor outgrowth. Wild-type p53-specific CTLs can apparently discriminate between p53-overexpressing tumor cells and normal tissue, indicating that widely expressed autologous molecules such as p53 can serve as a target for CTL-mediated immunotherapy of tumors.

Show MeSH
Related in: MedlinePlus