The Spontaneous CD8+ T-Cell Response to HLA-A2-Restricted NY-ESO-1b Peptide in Hepatocellular Carcinoma Patients

Shang, Xiaoying; Chen, Hongsong; Zhang, Hua–Gang; Pang, Xuewen; Qiao, Huan; Peng, Jie; Li, Qin; Fei, Ran; Mei, Ming-hui; Leng, Xi-sheng; Gnjatic, Sacha; Ritter, Gerd; Simpson, Andrew J.G.; Old, Lloyd J.; Chen, Weifeng

doi:10.1158/1078-0432.ccr-04-0502

Cited by 64 publications

(34 citation statements)

References 24 publications

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“…39 Furthermore, the existence of dysfunctional hTERT-specific T cells was accordant with previous reports of other tumor antigens. 39 Conversely, the frequency of hTERT 461 tetramer ϩ cells in tumors was quite high, and they produced IFN-␥. IFN-␥-producing T cells responding to other peptides hTERT 1088 , hTERT 845 , and hTERT 167 were also detected in tumors.…”

Section: Discussionsupporting

confidence: 85%

Cytotoxic T cell responses to human telomerase reverse transcriptase in patients with hepatocellular carcinoma

et al. 2006

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Human telomerase reverse transcriptase, hTERT, has been identified as the catalytic enzyme required for telomere elongation. hTERT is expressed in most tumor cells but seldom expressed in most human adult cells. It has been reported that 80% to 90% of hepatocellular carcinomas (HCCs) express hTERT, making the enzyme a potential target in immunotherapy for HCC. In the current study, we identified hTERT-derived, HLA-A*2402-restricted cytotoxic T cell (CTL) epitopes and analyzed hTERT-specific CTL responses in patients with HCC. Peptides containing the epitopes showed high affinity to bind HLA-A*2402 in a major histocompatibility complex binding assay and were able to induce hTERT-specific CTLs in both hTERT cDNA-immunized HLA-A*2402/K b transgenic mice and patients with HCC. The CTLs were able to kill hepatoma cell lines depending on hTERT expression levels in an HLA-A*2402-restricted manner and induced irrespective of hepatitis viral infection. The number of single hTERT epitope-specific T cells detected by ELISPOT assay was 10 to 100 specific cells per 3 ؋ 10 5 PBMCs, and positive T cell responses were observed in 6.9% to 12.5% of HCC patients. hTERT-specific T cell responses were observed even in the patients with early stages of HCC. The frequency of hTERT/tetramer ؉ CD8 ؉ T cells in the tumor tissue of patients with HCC was quite high, and they were functional. In conclusion, these results suggest that hTERT is an attractive target for T-cell-based immunotherapy for HCC, and the identified hTERT epitopes may be valuable both for immunotherapy and for analyzing host immune responses to HCC. (HEPATOLOGY 2006;43:1284-1294.) H epatocellular carcinoma (HCC) is the most frequent primary malignancy of the liver and has gained much clinical interest because of its increasing incidence. 1-3 Although current advances in therapeutic modalities have improved the prognosis of HCC patients, 4-6 the survival rate is still not satisfactory. One of the reasons for the poor prognosis is the high rate of recurrence after treatment. To protect against recurrence, tumor antigen-specific immunotherapy is an attractive strategy. Although many tumor-specific antigens have been identified in various cancers, the number of HCC-specific antigens known is still limited.Human telomerase reverse transcriptase, hTERT, has been identified as the catalytic enzyme required for telomere elongation. [7][8][9][10] Recently, several results regarding hTERT-specific cytotoxic T cell (CTL) responses were reported for humans and mice. [11][12][13][14][15][16][17][18][19][20] These reports revealed that hTERT-specific CTLs induced by stimulation with peptides or DNA-based immunization kill cancer cell lines that have high levels of hTERT, suggesting that hTERT-reactive T cell clones are not deleted from the human T cell repertoire and that hTERT may be a useful tumor-specific antigen as a target for T-cell-based immunotherapy for cancers. However, the existence of hTERT-specific CTLs and the relationship between immunological

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Section: Discussionsupporting

confidence: 85%

Cytotoxic T cell responses to human telomerase reverse transcriptase in patients with hepatocellular carcinoma

et al. 2006

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“…Epitope-specific tetramer + cells in PBMCs were also found in patients without IFN-γ ELISPOT responses, which was consistent with the findings of previous studies [39,40] and suggested the existence of dysfunctional epitope-specific T cells.…”

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confidence: 91%

P53, hTERT, WT-1, and VEGFR2 are the most suitable targets for cancer vaccine therapy in HLA-A24 positive pancreatic adenocarcinoma

Terashima

Mizukoshi

Arai

et al. 2014

Cancer Immunol Immunother

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Cancer vaccine therapy is one of the most attractive therapies as a new treatment procedure for pancreatic adenocarcinoma. Recent technical advances have enabled the identification of cytotoxic T lymphocyte (CTL) epitopes in various tumor-associated antigens (TAAs). However, little is known about which TAA and its epitope are the most immunogenic and useful for a cancer vaccine for pancreatic adenocarcinoma. We

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“…The category of CT antigens is the common target for tumour immunotherapy in clinical trials, for example, NY-ESO-1 is a potent CT antigen and its eliciting integrated cellular and humoral responses have been observed in vaccinated patients in clinical trials, with little or no toxicity (Jager et al, 2000;Chen et al, 2004;Davis et al, 2004). The spontaneous CD8 þ T-cell response to HLA-A2-restricted NY-ESO-1b peptide in HCC has been reported by our group (Shang et al, 2004), and our application for clinical trial of NY-ESO-1b peptide vaccine for the immunotherapy in HCC patients is under way.…”

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confidence: 66%

Identification and analysis of tumour-associated antigens in hepatocellular carcinoma

Wang

et al. 2005

Br J Cancer

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To identify tumour and tumour-associated antigens in patients with hepatocellular carcinoma (HCC) one may find potential diagnostic markers and immunotherapeutic targets. In the current study, 30 distinct antigens reactive with serum IgG from HCC patients were identified by serological analysis of cDNA expression libraries (SEREX). The mRNA expression patterns of 14 of these 30 antigens were altered in cancer as further revealed by cDNA microarray, with upregulation for nine and downregulation for five antigens. One of the upregulated antigens was cancer-testis (CT) antigen (CAGE), which had been previously reported to be expressed exclusively in normal gametogenic tissues and aberrantly expressed in a variety of cancer cells. In our study, CAGE mRNA was expressed in 39.4% of HCC patients, 73.3% of patients with gastric cancer and 30.8% of patients with colorectal cancer. Antibodies against CAGE protein were detected in approximately 5.1% of the sera from HCC patients, 8.3% of that from gastric cancer patients and 7.3% of that from colorectal cancer patients. The relative high incidence of CAGE in cancer cells makes it a potential target for vaccine design. Another antigen of great interest is transgelin 2. The overexpression of transgelin 2 mRNA in a large per cent (69%) of HCC points to its potential as a diagnostic marker for HCC.

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The Spontaneous CD8+ T-Cell Response to HLA-A2-Restricted NY-ESO-1b Peptide in Hepatocellular Carcinoma Patients

Cited by 64 publications

References 24 publications

Cytotoxic T cell responses to human telomerase reverse transcriptase in patients with hepatocellular carcinoma

Cytotoxic T cell responses to human telomerase reverse transcriptase in patients with hepatocellular carcinoma

P53, hTERT, WT-1, and VEGFR2 are the most suitable targets for cancer vaccine therapy in HLA-A24 positive pancreatic adenocarcinoma

Identification and analysis of tumour-associated antigens in hepatocellular carcinoma

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