Identification of polycomb group protein enhancer of zeste homolog 2 (EZH2)‐derived peptides immunogenic in HLA‐A24<sup>+</sup> prostate cancer patients

Ogata, Rie; Matsueda, Satoko; Yao, Akihisa; Noguchi, Masanori; Itoh, Kyogo; Harada, Mamoru

doi:10.1002/pros.20078

Cited by 30 publications

(25 citation statements)

References 27 publications

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“…Functional EZH2-specific T cells have previously been isolated from patients with prostate cancer using HLA-A2402-restricted peptides. These effectors were shown to be cytotoxic against the C1R-A24 subline of C1R lymphoma and also the prostate cancer cell line LNCaP, which had been stably transfected with the HLA-A2402 gene (Ogata et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

The polycomb group proteins, BMI-1 and EZH2, are tumour-associated antigens

Steele

Torr

Noakes³

et al. 2006

Br J Cancer

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We used SEREX technology to identify novel tumour-associated antigens in patients with primary hepatocellular carcinoma and found serological responses to the polycomb group (PcG) protein BMI-1, which is overexpressed in a range of different tumour types. Further studies identified T-cell responses to both BMI-1 and another PcG protein, EZH2, in cancer patients and at relatively lower levels in some normal donors. We next identified several CD8 þ T-cell epitopes derived from BMI-1 and EZH2 and demonstrated that EZH2-derived peptides elicited more significant interferon-g (IFN-g) release than BMI-1-derived peptides. That CD8 þ T cells were responsible for the observed responses was confirmed for EZH2 by both IFN-g capture assays and tetramer staining using an HLA-A0201-restricted, EZH2-derived YMSCSFLFNL (aa 666 -674) epitope. The ability of YMSCSFLFNL (aa 666 -674) to stimulate the in vitro expansion of specific T cells from peripheral blood lymphocytes was greatly enhanced when the CD25 þ T-cell population was depleted. EZH2-specific cytotoxic T lymphocyte clones specific for two HLA-A0201 epitopes were generated and found to recognise endogenously processed EZH2 in both HLA-matched fibroblasts and tumour cell lines. Given the widespread overexpression of PcG proteins in cancer and their critical role in oncogenesis, these data suggest that they may be useful targets for cancer immunotherapy.

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Section: Discussionmentioning

confidence: 99%

The polycomb group proteins, BMI-1 and EZH2, are tumour-associated antigens

Steele

Torr

Noakes³

et al. 2006

Br J Cancer

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“…They are listed in Table 1. SART3 93-101, SART3 109-118, CypB 91-99, Lck 486-494, Lck 488-497, MRP3 1293 -1302, PAP 213-221, EZH2 291-299, PSCA 76-84 and PSA 248-257 peptides have been reported to induce HLA-A24-restricted and tumor-specific CTL in PBMC of cancer patients (15)(16)(17)(18)(19)(20)(21) and were used for HLA-A24 + patients. SART3 302-310, Lck 246 -254, WHS 103 -111, HNR 140-148, MAP 294-302, UBE 43-51, EIF 51-59, EGFR 479-488, PSA 170-178 and HER2/ neu 484-493 peptides have been reported to induce HLA-A2-restricted and tumor-specific CTL in PBMC of cancer patients (22)(23)(24)(25)(26)(27) and were used for HLA-A2 + patients.…”

Section: Methodsmentioning

confidence: 99%

Immunological evaluation of personalized peptide vaccination in combination with a 5‐fluorouracil derivative (TS‐1) for advanced gastric or colorectal carcinoma patients

et al. 2007

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The aim of the present study was to investigate the safety and immunological responses of personalized peptide vaccination in combination with oral administration of a 5-fluorouracil derivative (TS-1) in advanced gastric or colorectal carcinoma patients. Eleven patients (four with gastric cancer and seven with colorectal cancer) who failed to improve by prior TS-1-based chemotherapies were enrolled in this study. Peptides to be administered to patients were determined based on the presence of peptide-specific cytotoxic T lymphocyte ( (1) Cancer vaccines have emerged as a promising therapeutic approach, (2) but their clinical responses have been limited.(3) In order to develop a new treatment modality, we recently devised a new regime of peptide-based vaccination that consists of measuring pre-existing CTL precursors and IgG reactive to many kinds of vaccine candidates, followed by administration. (4)(5)(6)(7)(8) In addition, we recently reported the benefits of the combination of this type of peptide vaccination with a low dose of estramustine phosphate in hormone refractory prostate cancer patients.(9) This chemoimmunotherapy may break through the impasse in the clinical efficacy of cancer vaccines.TS-1 is an oral fluoropyrimidine derivative consisting of Tegafur (FT) and two modulators, 5-chloro-2,4-dihydroxypyrimidine (CDHP) and potassium oxonate (Oxo). FT is a prodrug of 5-fluorouracil (5-FU) and CDHP is a reversible competitive inhibitor of an enzyme involved in the degradation of 5-FU. Therefore, the FT-derivative 5-FU remains in tumor tissue a long time, resulting in an enhanced antitumor effect.(10,11) Indeed, TS-1 has been reported to be effective at prolonging the survival of patients with advanced gastric cancer.(12) Furthermore, TS-1 can be administered as an oral formulation that permits treatment on an outpatient basis, leading to improvement in the quality of life (QOL) of patients. In the present study, we investigated the safety and immunological responses of personalized peptide vaccination in combination with the oral administration of TS-1 in advanced gastric or colorectal carcinoma patients. Materials and MethodsPatients and eligibility criteria. The study protocol was approved by the Institutional Ethical Review Boards of Hokkaido University, Okayama University and Kurume University. Complete written informed consent was obtained from all patients at the time of enrolment. According to the protocol, patients were confirmed to be HLA-A24 or HLA-A2 positive and had a histologically confirmed lesion of gastric or colorectal carcinoma. In HLA-A2 + patients, their HLA-A2 genotypes were determined using sequence-specific oligonucleotide DNA typing after polymerase chain reaction. All patients had failed to improve by prior chemotherapy with TS-1. The other eligibility criteria included an age of 85 years or less, serum creatinine of less than 1.4 mg/dL, bilirubin of less than 1.5 mg / dL, a platelet count of 100 000 µL or more, hemoglobin of 8.0 g / dL or more, and total white blood cell count (W...

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“…1). Figure 1 shows the distributions of signal intensities for the fractions with the top three M2 scores for the nonorgan-confined (M2 ranging from 12-15) and the organconfined samples (M2 ranging from [15][16][17]. To get some idea of the M2 scores that would be produced by chance, one may define a threshold as the second-highest cancer sample and count the number of normal samples above that threshold.…”

Section: Identifying Fractions With Cancer-associated Immunoreactivitymentioning

confidence: 99%

“…For example, antibodies have been detected in serum or plasma of prostate cancer patients against proteins such as alpha-methyl-acyl-CoA racemase (AMACR) [15], enhancer of zeste homolog 2 (EZH2) [16], PSA [17], HER-2/neu [17], secretory granules of the prostate [18], and lens epithelium-derived growth factor p75 (LEDGF/p75) [19]. The high prevalence of a tumor-associated immune response in patients with prostate cancers was shown in a study of a panel of six tumor-associated antigens [20] with a positive response in cancers at 92.5% vs. 14.8% in normals, as well as with microarrays of phage-displayed polypeptides at a specificity of 88.2% and 81.6% sensitivity [7].…”

Section: Introductionmentioning

confidence: 99%

An experimental strategy for quantitative analysis of the humoral immune response to prostate cancer antigens using natural protein microarrays

Forrester

Qiu

Mangold

et al. 2007

Proteomics Clinical Apps

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The identification of human tumor antigens has potential utility in the diagnosis and treatment of cancers. We demonstrate here a complete strategy to profile immunoreactivity and identify tumor antigens from proteins derived from tumor cell lines. Microarrays of proteins produced from 2-D LC fractionation of prostate tumor cell-line lysates were used to profile immunoreactivity in the sera of prostate cancer patients and control subjects. Cancer-associated immunoreactivity to distinct groups of chromatography fractions was present in about 50% of the patients, with greater immunoreactivity present in patients with non-organ-confined cancer than in patients with organ-confined cancer. We grouped the immunoreactive fractions by similarities in elution order and patterns of immunoreactivity to guide and interpret the MS analysis of selected fractions, which was used to identify the proteins that may be responsible for the immunoreactivity. As a complementary method to further characterize and validate the immunoreactivity of the proteins identified by mass spectrometry, we demonstrate the use of focused microarrays of recombinant proteins. Disease-associated immunoreactivity was confirmed for one of the identified proteins, human Kallikrein 11. These results demonstrate a practical approach to screening, identifying, and validating immunoreactive proteins that could be applied to diverse studies on humoral immune responses.

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Identification of polycomb group protein enhancer of zeste homolog 2 (EZH2)‐derived peptides immunogenic in HLA‐A24⁺ prostate cancer patients

Abstract: These EZH2-291 to -299 and EZH2-735 to -742 peptides could be promising candidates for peptide-based immunotherapy for HLA-A24+ prostate cancer patients with metastases.

Cited by 30 publications

References 27 publications

The polycomb group proteins, BMI-1 and EZH2, are tumour-associated antigens

The polycomb group proteins, BMI-1 and EZH2, are tumour-associated antigens

Immunological evaluation of personalized peptide vaccination in combination with a 5‐fluorouracil derivative (TS‐1) for advanced gastric or colorectal carcinoma patients

An experimental strategy for quantitative analysis of the humoral immune response to prostate cancer antigens using natural protein microarrays

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Identification of polycomb group protein enhancer of zeste homolog 2 (EZH2)‐derived peptides immunogenic in HLA‐A24+ prostate cancer patients

Abstract: These EZH2-291 to -299 and EZH2-735 to -742 peptides could be promising candidates for peptide-based immunotherapy for HLA-A24+ prostate cancer patients with metastases.

Cited by 30 publications

References 27 publications

The polycomb group proteins, BMI-1 and EZH2, are tumour-associated antigens

The polycomb group proteins, BMI-1 and EZH2, are tumour-associated antigens

Immunological evaluation of personalized peptide vaccination in combination with a 5‐fluorouracil derivative (TS‐1) for advanced gastric or colorectal carcinoma patients

An experimental strategy for quantitative analysis of the humoral immune response to prostate cancer antigens using natural protein microarrays

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Identification of polycomb group protein enhancer of zeste homolog 2 (EZH2)‐derived peptides immunogenic in HLA‐A24⁺ prostate cancer patients