In vitro induction of human cytotoxic T lymphocyte responses against peptides of mutant and wild‐type p53

Houbiers, J. G. A.; Nijman, Hans W.; Burg, Sjoerd H. van der; Drijfhout, Jan W.; Kenemans, P.; Velde, Cornelis J.H. van de; Brand, Anneke; Momburg, Frank; Kast, W. Martin; Melief, C. J. M.

doi:10.1002/eji.1830230905

Cited by 228 publications

(147 citation statements)

References 54 publications

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“…In contrast, CD8 ϩ T cells recognizing peptide 261-269 of p53 had not been tolerized and displayed CTL activity after peptide immunization. Similarly, other investigators reported that CD8 ϩ and CD4 ϩ T cell lines generated from healthy humans contain self-p53 peptide-reactive T cells (38,39). Together with our study, these observations show that during thymic selection certain portions of selfp53 are well processed and presented (dominant-self) and induce CD4 and CD8 T cell tolerance.…”

Section: Discussionsupporting

confidence: 90%

CD4+ T Cell Responses to Self- and Mutated p53 Determinants During Tumorigenesis in Mice

Fedoseyeva

Boisgerault

Anosova

et al. 2000

The Journal of Immunology

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We analyzed CD4+ T helper responses to wild-type (wt) and mutated (mut) p53 protein in normal and tumor-bearing mice. In normal mice, we observed that although some self-p53 determinants induced negative selection of p53-reactive CD4+ T cells, other p53 determinants (cryptic) were immunogenic. Next, BALB/c mice were inoculated with J774 syngeneic tumor cell line expressing mut p53. BALB/c tumor-bearing mice mounted potent CD4+ T cell responses to two formerly cryptic peptides on self-p53. This response was characterized by massive production of IL-5, a Th2-type lymphokine. Interestingly, we found that T cell response was induced by different p53 peptides depending upon the stage of cancer. Mut p53 gene was shown to contain a single mutation resulting in the substitution of a tyrosine by a histidine at position 231 of the protein. Two peptides corresponding to wt and mutated sequences of this region were synthesized. Both peptides bound to the MHC class II-presenting molecule (Ed) with similar affinities. However, only mut p53.225–239 induced T cell responses in normal BALB/c mice, a result strongly suggesting that high-affinity wt p53.225–239 autoreactive T cells had been eliminated in these mice. Surprisingly, CD4+ T cell responses to both mut and wt p53.225–239 peptides were recorded in J774 tumor-bearing mice, a phenomenon attributed to the recruitment of low-avidity p53.225–239 self-reactive T cells.

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Section: Discussionsupporting

confidence: 90%

CD4+ T Cell Responses to Self- and Mutated p53 Determinants During Tumorigenesis in Mice

Fedoseyeva

Boisgerault

Anosova

et al. 2000

The Journal of Immunology

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“…The peptides were the HLA-A*0201-binding peptide STPPPGTRV, corresponding to WT p53 149-157 and LLGRNSFEV corresponding to WT p53 264-272 peptide, both representing wellestablished HLA-A*0201-restricted T cell epitopes. [18][19][20] The specificity of p53 tetramers used in this study was previously confirmed by competition of CD3 binding, staining against respective anti-p53-specific CTL lines and by the lack of staining with irrelevant CTL or HLA-A2 2 PBMC of healthy donors. [21][22][23][24] To minimize background staining, each tetramer was titered and used at the lowest concentration that still gave a clearly discernible positive population.…”

Section: Tetrameric Peptide-mhc Class I Complex (Tetramer) Assaysupporting

confidence: 62%

Increased frequencies of CD8+ T lymphocytes recognizing wild‐type p53‐derived epitopes in peripheral blood correlate with presence of epitope loss tumor variants in patients with hepatocellular carcinoma

Cicinnati

Zhang

et al. 2006

Intl Journal of Cancer

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Wild-type (WT) sequence p53 peptides are attractive candidates for broadly applicable cancer vaccines. The aim of this study was to evaluate the potential of a WT p53-based immunotherapeutic approach for patients with hepatocellular carcinoma (HCC). Circulating CD8 1 T cells specific for WT p53 [149][150][151][152][153][154][155][156][157] and WT p53 [264][265][266][267][268][269][270][271][272] HLA-A*0201 restricted epitopes were directly identified in the peripheral blood by the use of peptide/HLA-A2.1 tetramers in 24 HCC patients. Cytotoxic T lymphocyte (CTL) activity after WT p53 peptide-specific stimulation was assessed by analysis of granzyme B and interferon-gamma mRNA transcription, using a quantitative real-time polymerase chain reaction assay. Tumor immunophenotyping was performed to evaluate the p53 status, the expression of major histocompatibility complex (MHC) and costimulatory molecules in freshly isolated tumor cells. HCC patients exhibited significantly higher frequencies of WT p53-specific memory CD8 1 T cells and stronger WT p53-specific CTL activity, when compared with healthy controls. Increased frequencies of p53-specific CD8 1 T cells and their activity correlated with selective HLA-A2 allele loss and reduced costimulatory molecule expression of tumor cells. Moreover, augmented numbers of p53-specific T cells coincided with high MHC class II expression in tumor cells but were inversely related to the T status of the tumor node metastasis staging system. Our results indicate the existence of natural immunosurveillance and tumor immune evasion, involving a T cell response against WT p53 tumor antigen in patients with HCC. These findings may have important implications for the future development of cancer vaccines. ' 2006 Wiley-Liss, Inc.Key words: cytotoxic T lymphocyte; hepatocellular carcinoma; immunotherapy; p53; tumor escape Hepatocellular carcinoma (HCC) represents the third most common cause of cancer in the world, and its incidence continues to increase. 1,2 The 5-year disease-free survival rate after liver resection is extremely poor because of frequent tumor recurrence. 3,4 Recent strategies using liver transplantation for selected patients with early tumor stage have shown more promising results. 5,6 However, liver resection or local tumor ablation remain the sole treatment options for the vast majority of patients; both adjuvant systemic chemotherapy and hormonal treatment have failed to significantly impact on patient survival. 7 New adjuvant treatment modalities are therefore needed to lower the incidence of tumor recurrence in patients after liver resection or local tumor treatment. Previously, it has been reported that the adjuvant adoptive transfer of ex vivo activated autologous lymphocytes in patients, who underwent liver resection for HCC, was associated with significantly increased recurrence-free survival. 8 These findings underline the important role of the adaptive cellular immune response for survival in patients with HCC and provide the rationale for the development ...

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“…Several groups have been able to establish human CTL cultures from healthy HLA-A2 ϩ donors recognizing the epitope L9V spanning position 264 -272 of the p53 molecule, 11,13,22 and our group was the first to demonstrate killing of natural tumor cell targets by an in vitro established p53-specific CTL clone. 12 Subsequently, similar results were reported from a study by Gnjatic et al 13 describing the recognition of several natural tumor cell lines by an L9V-specific CTL line.…”

Section: Ctl Killing Of Natural Targetsmentioning

confidence: 96%

Specific killing of P53 mutated tumor cell lines by a cross-reactive human HLA-A2-restricted P53-specific CTL line

et al. 2001

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p53 is upregulated in the majority of spontaneous tumors and the HLA class I molecule HLA-A2 is expressed by approximately 50% of the caucasians. Potentially, these facts make HLA-A2-binding p53 peptides for CTL-inducing immunotherapy applicable to a broad range of cancer patients. In our study, we investigated the CTL-inducing capacity of autologous monocyte-derived dendritic cells (DC) maturated by exposure to CD40L and pulsed with a pool of 4 wild-type, HLA-A2-binding p53 peptides, and the p53-specific CD8 ؉ CTL lines established from healthy HLA-A2-positive donors were characterized. Reactivity to p53 65-73 and p53 [187][188][189][190][191][192][193][194][195][196][197] peptides was obtained in the T-cell lines. Interestingly, cold target inhibition experiments demonstrated that the simultaneous recognition of the 2 peptides was the result of crossreactivity, which was confirmed by killing experiments at the clonal CTL level. Furthermore, 4 HLA-A2 ؉ p53-mutated tumor cell lines were lysed by the CTL line, indicating that these peptides are endogenously processed and presented on HLA-A2 molecule. Thus, monocyte-derived DC pulsed with a pool of peptides are able to induce CTL reactivity to wildtype p53 peptides presented by several cancer cell lines. In addition, the recognition of 2 different p53 peptides by the same CTL clone suggests a promiscuous peptide recognition by the TCR involved. Taken together, these in vitro results suggest that vaccination with autologous DC pulsed with multiple p53 epitopes may induce an effective tumor-specific CTL response in vivo with the potential to eradicate p53-upregulated spontaneously occurring tumors. © 2001 Wiley-Liss, Inc. Key words: p53; cytotoxic T-lymphocytes; HLA-A2; dendritic cellsThe cell cycle regulating protein p53 binds to DNA with coincidental nucleotide misincorporations and leads to cell cycle arrest and DNA repair. 1 The involvement of p53 at this crucial checkpoint in the cell division is probably reflected by the fact that inactivating mutations in the p53 genome are found in the majority of human cancer diseases. 2,3 The rationale behind a broadly applicable vaccination immunotherapy of human cancer disease with HLA-A2 binding p53 peptides is based on the high levels of wild-type p53 demonstrated in p53-mutated tumor cells 4,5 and the presence of peptide residues in the p53 protein that bind to the common HLA class I molecule HLA-A2. 6 A vaccination protocol based on wild-type peptides allows one to circumvent the limitations of strategies focused on the specific nonself peptides that arise through the variable p53 mutations found in single individuals.Recently, several clinical studies on cancer immunotherapy using different approaches to activate cytotoxic T cells in vivo [7][8][9] or ex vivo 10 recognizing individual tumor antigens have been highly successful. These results underscore the efficiency of the immune system in controlling tumor growth and emphasize the importance of characterizing CTL specific to general tumor antigens. Four studies on...

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In vitro induction of human cytotoxic T lymphocyte responses against peptides of mutant and wild‐type p53

Cited by 228 publications

References 54 publications

CD4+ T Cell Responses to Self- and Mutated p53 Determinants During Tumorigenesis in Mice

CD4+ T Cell Responses to Self- and Mutated p53 Determinants During Tumorigenesis in Mice

Increased frequencies of CD8+ T lymphocytes recognizing wild‐type p53‐derived epitopes in peripheral blood correlate with presence of epitope loss tumor variants in patients with hepatocellular carcinoma

Specific killing of P53 mutated tumor cell lines by a cross-reactive human HLA-A2-restricted P53-specific CTL line

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