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

Würtzen, Peter Adler; Pedersen, Lars Østergaard; Poulsen, Hans Skovgaard; Claësson, Mogens H.

doi:10.1002/ijc.1417

Cited by 20 publications

(21 citation statements)

References 36 publications

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“…We have recently demonstrated that efficient activation of p53-specific CTLs can be obtained through DC presentation of several p53 peptides in combination. 22 In the present investigation, we included the following 3 p53-derived wild-type peptides: a recently predicted HLA-A2 binding peptide p53 103-111 (Y9L), 27 peptide p53 139 -147 (K9V) 20 and the previously described peptide p53 149 -157 (S9V). 28 Immunization with these peptides was previously shown to induce strong CTL reactivity in vivo in a HLA-A2 transgenic mouse model system.…”

Section: Abstract: Cytotoxic T-lymphocytes; Cancer; P53-epitope; Hla-a2mentioning

confidence: 99%

“…22 Briefly, adherent monocytes from freshly isolated PBMC were cultured in RPMI 1640 medium (GibcoBRL, UK) supplemented with 5% v/v ABserum (RH, Copenhagen, Denmark), 0.3 g/ml L-glutamine, 100 units/ml penicillin and 0.1 mg/ml streptomycin (referred to as AB-medium) supplemented with 250 U/ml hrIL-4 (R & D Systems, Minneapolis, MN) and 500 U/ml hrGM-CSF (Leucomax, Novartis/Schering-Plough, Basel, Switzerland) in 6-well plates (Nunc, Roskilde, Denmark) for 9 -11 days with the addition of hrCD40LT, 1 g/ml, (Immunex Corporation, Seattle, WA) for the last 3 days of the culture period.…”

Section: Generation Of DCmentioning

confidence: 99%

“…22 Briefly, freshly isolated PBMC were stimulated with autologous irradiated (3,000 Rad) DC loaded with a pool of p53 peptides (Y9L, K9V and S9V) at a concentration of 10 M in 24-well plates in 1 ml AB-medium/ well containing 20 U/ml rhIL-4 and 5 ng/ml rhIL-7 (Peprotech EC, London, UK). The T-cell cultures were depleted for CD4 ϩ cells by Dynabead separation (according to the manufacturers instructions) at day 10 and restimulated with peptide pulsed autologous DC and autologous PBMC in AB-medium supplemented with rhIL-4 and rhIL-7.…”

Section: Generation Of Ctl Linesmentioning

confidence: 99%

“…20 However, anti-p53 peptide CTL reactivity combined with the recognition of spontaneous tumor cells have only been described towards 4 p53 protein-derived wild-type peptides, p53 65-73, 149 -157, 187-197 and 264 -272. [21][22][23][24][25] These CTLs were generated in highly different culture systems based on stimulations with peptides pulsed on the TAP deficient cell line T2, 11,20,23 autologous dendritic cells in combination with different cytokine mixtures 21,22,25 or with peptides added directly to the responder PBMC in combination with exposure of Th cells towards PPD. 24 However, the low frequency of CTL precursors in vivo specific to individual p53 peptides 26 suggests that protocols for anti-p53 CTL generation ex vivo and for vaccination should be based on several p53 peptides in combination to improve the chance for efficient CTL-activation.…”

mentioning

confidence: 99%

“…24 However, the low frequency of CTL precursors in vivo specific to individual p53 peptides 26 suggests that protocols for anti-p53 CTL generation ex vivo and for vaccination should be based on several p53 peptides in combination to improve the chance for efficient CTL-activation. Moreover, the lack of a direct connection between p53 mutations, overexpression of the protein and presentation of p53 peptides that lead to tumor cell killing 22,23,28 makes it difficult to predict peptides relevant for the cancer disease of the individual patient. This may also be circumvented through inclusion of several p53-peptides in cancer vaccines.…”

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confidence: 99%

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A HLA‐A2 restricted human CTL line recognizes a novel tumor cell expressed p53 epitope

Würtzen

Claësson

2002

Intl Journal of Cancer

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A p53 peptide-specific CTL line was generated through stimulation with autologous monocyte-derived dendritic cells (DC) pulsed with wild-type HLA-A2 binding p53 derived peptides. A p53 peptide-specific CD8؉ CTL line was established from a healthy HLA-A2 positive donor. The CTL line was characterized with respect to specificity, affinity and killing of cell lines derived from p53 mutated spontaneous tumors. The CTL line demonstrated lysis of p53 139 -147 pulsed target cells and cold target inhibition experiments as well as antibody blocking confirmed that the killing was epitopespecific, HLA-A2 restricted and dependent on CD8-binding. Interestingly, the affinity of the CTL line was only in the micromole per liter range and target cells pulsed with less than 0.01 M peptide were not recognized. Furthermore, 3 HLA-A2؉ p53 mutated tumor cell lines were efficiently lysed by the CTL line, indicating that this novel p53 peptide epitope is endogenously processed and presented by the HLA-A2 molecules of the tumor cells. In conclusion, CTL reactivity towards a wild-type p53 peptide was revealed through induction with DC pulsed with a pool of HLA-A2 binding p53 peptides. In addition, the CTL line, which expressed relatively low affinity for the HLA-A2/peptide complex, was able to kill 3 different HLA-A2؉ p53 mutated tumor cell lines. The present and our previous observations expand the number of p53-derived peptides suitable for vaccination protocols for cancer patients with p53 positive tumors. © 2002 Wiley-Liss, Inc. Key words: cytotoxic T-lymphocytes; cancer; p53-epitope; HLA-A2Recent progress in the determination of tumor specific antigens and their potential as possible immunological targets has lead to the description of antigens associated with cell lineage and differentiation of neoplastic cells such as MAGE-1 and MAGE-3, 1 tyrosinase, gp100, Melan-A/MART-1 and gp75, 2 BAGE, 3 MUC-1, 4 Her-2/neu, 5 CEA 6 and Ig-idiotypes 7 as well as antigens generally associated with tumors, such as p53, 8 telomerase, 9 and survivin 10 and antigens that represent mutated peptides derived from p53 11 and Ras. 12 The latter set of peptides and the Ig isotypes represent true, individual tumor antigens. Peptide epitopes of these tumor-associated antigens are all intended for vaccination therapy of cancer patients and very promising results have been obtained during the last decade. [13][14][15][16] p53 plays a key role in the G 0 -G 1 cell cycle regulation and mutations in the p53 genome are found in more than 50% of human cancer diseases. 17,18 The p53 mutations lead to changes in p53 protein turnover and subsequent p53 accumulation in the tumor cells. 19 Since the early 1990s, a number of p53 proteinderived peptides with high affinity for the common HLA class I molecule HLA-A2, present in approx. 50% of all caucasians, have been predicted and their HLA-A2 binding has been confirmed by different methods. 20 However, anti-p53 peptide CTL reactivity combined with the recognition of spontaneous tumor cells have only been described toward...

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Section: Abstract: Cytotoxic T-lymphocytes; Cancer; P53-epitope; Hla-a2mentioning

confidence: 99%

Section: Generation Of DCmentioning

confidence: 99%

Section: Generation Of Ctl Linesmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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A HLA‐A2 restricted human CTL line recognizes a novel tumor cell expressed p53 epitope

Würtzen

Claësson

2002

Intl Journal of Cancer

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P53‐specific T cell responses in patients with malignant and benign ovarian tumors: Implications for p53 based immunotherapy

Lambeck

Leffers

Hoogeboom

et al. 2007

Intl Journal of Cancer

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Despite intensive treatment, 70% of the ovarian cancer patients will develop recurrent disease, emphasizing the need for new approaches such as immunotherapy. A promising antigenic target for immunotherapy in ovarian cancer is the frequently overexpressed p53 protein. The aim of the study was to evaluate the nature and magnitude of the baseline anti-p53 immune response in ovarian cancer patients. P53-specific T cell responses were detected in both half of the ovarian cancer patients as in the group of control subjects, consisting of women with benign ovarian tumors and healthy controls. Importantly, while in the control group p53-specific immunity was detected among the CD45RA 1 na€ ıve subset of T cells only, the p53-specific T-cell responses in ovarian cancer patients were also present in the CD45RO 1 memory T-cell subset, suggesting that in the cancer patients sufficient amounts of cancer-derived p53 was presented to induce the formation of a p53-specific memory T-cell response. Further characterization of the p53-specific memory T-cell responses revealed that in addition to the type 1 cytokine IFN-c also the type 2 cytokines IL-4 and IL-5, as well as the immunosuppressive cytokine IL-10 were produced. Notably, p53-specific T cells were not only detected in the peripheral blood, but also among tumor infiltrating lymphocytes and in tumor-draining lymph nodes. In conclusion, the existence of a weak mixed T-helper type 1 and 2 p53-specific T-cell repertoire supports the rationale of using p53 long peptides in vaccination strategies aiming at the induction of p53-specific Th1/ CTL immunity. ' 2007 Wiley-Liss, Inc.

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Peptide Vaccines Against Cancer

Berzofsky¹,

Oh²,

Terabe³

2005

Cancer Treatment and Research

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

Cited by 20 publications

References 36 publications

A HLA‐A2 restricted human CTL line recognizes a novel tumor cell expressed p53 epitope

A HLA‐A2 restricted human CTL line recognizes a novel tumor cell expressed p53 epitope

P53‐specific T cell responses in patients with malignant and benign ovarian tumors: Implications for p53 based immunotherapy

Peptide Vaccines Against Cancer

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