Identification and Enhancement of HLA-A2.1-Restricted CTL Epitopes in a New Human Cancer Antigen-POTE

Huang, Yi Hsiang; Terabe, Masaki; Pendleton, C. David; Khursigara, Deborah Stewart; Bera, Tapan K.; Pastan, Ira; Berzofsky, Jay A.

doi:10.1371/journal.pone.0064365

Cited by 16 publications

(14 citation statements)

References 43 publications

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“…However, it remains unclear whether the HTNV-NP FA9 epitope can induce a strong CD8 + T-cell immunity against HTNV infection in vivo. Humanized mice, which are mice engrafted with human tissue and/or are engineered to express human genes, are considered powerful tools for studying species-restricted pathogen that can induce in vivo human immunity (29)(30)(31). Therefore, a "humanized" HLA-A2.1/K b transgenic (Tg) mouse model that expresses a chimeric monochain of HLA-A*02 infected with HTNV would be an ideal virus replication model to explore the effect of in vivo responses primed by epitope FA9.…”

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confidence: 99%

Structure and Function of HLA-A*02-Restricted Hantaan Virus Cytotoxic T-Cell Epitope That Mediates Effective Protective Responses in HLA-A2.1/Kb Transgenic Mice

Cheng

Yuan

et al. 2016

Front. Immunol.

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Hantavirus infections cause severe emerging diseases in humans and are associated with high mortality rates; therefore, they have become a global public health concern. Our previous study showed that the CD8+ T-cell epitope aa129–aa137 (FVVPILLKA, FA9) of the Hantaan virus (HTNV) nucleoprotein (NP), restricted by human leukocyte antigen (HLA)-A*02, induced specific CD8+ T-cell responses that controlled HTNV infection in humans. However, the in vivo immunogenicity of peptide FA9 and the effect of FA9-specific CD8+ T-cell immunity remain unclear. Here, based on a detailed structural analysis of the peptide FA9/HLA-A*0201 complex and functional investigations using HLA-A2.1/Kb transgenic (Tg) mice, we found that the overall structure of the peptide FA9/HLA-A*0201 complex displayed a typical MHC class I fold with Val2 and Ala9 as primary anchor residues and Val3 and Leu7 as secondary anchor residues that allow peptide FA9 to bind tightly with an HLA-A*0201 molecule. Residues in the middle portion of peptide FA9 extruding out of the binding groove may be the sites that allow for recognition by T-cell receptors. Immunization with peptide FA9 in HLA-A2.1/Kb Tg mice induced FA9-specific cytotoxic T-cell responses characterized by the induction of high expression levels of interferon-γ, tumor necrosis factor-α, granzyme B, and CD107a. In an HTNV challenge trial, significant reductions in the levels of both the antigens and the HTNV RNA loads were observed in the liver, spleen, and kidneys of Tg mice pre-vaccinated with peptide FA9. Thus, our findings highlight the ability of HTNV epitope-specific CD8+ T-cell immunity to control HTNV and support the possibility that the HTNV-NP FA9 peptide, naturally processed in vivo in an HLA-A*02-restriction manner, may be a good candidate for the development HTNV peptide vaccines.

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confidence: 99%

Structure and Function of HLA-A*02-Restricted Hantaan Virus Cytotoxic T-Cell Epitope That Mediates Effective Protective Responses in HLA-A2.1/Kb Transgenic Mice

Cheng

Yuan

et al. 2016

Front. Immunol.

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“…These findings indicate that the POTE gene family encodes a family of pro-apoptotic proteins [21]. Yi-Hsiang Huang et al determined peptide modification can enhance the immunogenicity of POTE epitopes to induce T cells that kill human cancer cells, this result suggest that POTE may also be a molecular target for cancer immunotherapy [22]. In the last few years the researches for CT antigen have made some progress.…”

Section: Discussionmentioning

confidence: 97%

Serum levels of the cancer-testis antigen POTEE and its clinical significance in non-small cell lung cancer.

Wang

Ren

et al. 2015

JCO

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Background POTEE (POTE ankyrin domain family, member E) is a newly identified cancer-testis antigen that has been found to be expressed in a wide variety of human cancers including cancers of the colon, prostate, lung, breast, ovary, and pancreas. Aim To measure the serum levels of POTEE in patients with non-small-cell lung cancer (NSCLC) and to explore the clinical significance of POTEE in NSCLC. Patients and Methods 104 NSCLC patients, 66 benign lung disease patients and 80 healthy volunteers were enrolled in this study from May 2013 to February 2014. Serum POTEE levels were measured using enzyme-linked immunosorbent assay (ELISA). Numerical variables were recorded as means ± standard deviation (SD) and analyzed by independent t tests. Categorical variables were calculated as rates and were analyzed using a χ 2 test or Fisher's exact test. Survival curves were estimated and compared using the Kaplan-Meier method and logrank tests. Results Serum POTEE levels were significantly higher in NSCLC patients than in benign lung disease patients and healthy controls (mean ± SD [pg/ml], 324.38± 13.84 vs. 156.93 ± 17.38 and 139.09 ± 15.80, P<0.001) and were significantly correlated with TNM stage. Survival analysis revealed that patients with low serum POTEE had longer progression-free survival (PFS) than those with high serum POTEE (P=0.021). Cox multivariate analysis indicated that POTEE was an independent prognostic factor of progression-free survival (P =0.009, hazard ratio, 2.440).

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“…These results are consistent with previous reports that improving the binding affinity of peptides to MHC class I can result in enhanced immunogenicity of epitopes. [33][34][35][36][37] Increasing the density of peptide-MHC complexes on antigen-presenting cells is important for enhancing in vivo immunogenicity. We demonstrated that the 1Y3W6L and 1Y6V peptides elicited increased immune responses against T2 cells pulsed with a low concentration of native peptide and against tumor cells endogenously expressing hPEBP4 at low E: T ratios.…”

Section: Discussionmentioning

confidence: 99%

A modified HLA-A*0201-restricted CTL epitope from human oncoprotein (hPEBP4) induces more efficient antitumor responses

Sun

Shi

et al. 2018

Cell Mol Immunol

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We previously identified human phosphatidylethanolamine-binding protein 4 (hPEBP4) as an antiapoptotic protein with increased expression levels in breast, ovarian and prostate cancer cells, but low expression levels in normal tissues, which makes hPEBP4 an attractive target for immunotherapy. Here, we developed hPEBP4-derived immunogenic peptides for inducing antigen-specific cytotoxic T lymphocytes (CTLs) targeting breast cancer. A panel of hPEBP4-derived peptides predicted by peptide-MHC-binding algorithms was evaluated to characterize their HLA-A2.1 affinity and immunogenicity. We identified a novel immunogenic peptide, P40-48 (TLFCQGLEV), that was capable of eliciting specific CTL responses in HLA-A2.1/K transgenic mice, as well as in peripheral blood lymphocytes from breast cancer patients. Furthermore, amino-acid substitutions in the P40-48 sequence improved its immunogenicity against hPEBP4, a self-antigen, thus circumventing tolerance. We designed peptide analogs by preferred auxiliary HLA-A*0201 anchor residue replacement, which induced CTLs that were crossreactive to the native peptide. Several analogs were able to stably bind to HLA-A*0201 and elicit specific CTL responses better than the native sequence. Importantly, adoptive transfer of CTLs induced by vaccination with two analogs more effectively inhibited tumor growth than the native peptide. These data indicate that peptide analogs with high immunogenicity represent promising candidates for peptide-mediated therapeutic cancer vaccines.

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Identification and Enhancement of HLA-A2.1-Restricted CTL Epitopes in a New Human Cancer Antigen-POTE

Cited by 16 publications

References 43 publications

Structure and Function of HLA-A*02-Restricted Hantaan Virus Cytotoxic T-Cell Epitope That Mediates Effective Protective Responses in HLA-A2.1/Kb Transgenic Mice

Structure and Function of HLA-A*02-Restricted Hantaan Virus Cytotoxic T-Cell Epitope That Mediates Effective Protective Responses in HLA-A2.1/Kb Transgenic Mice

Serum levels of the cancer-testis antigen POTEE and its clinical significance in non-small cell lung cancer.

A modified HLA-A*0201-restricted CTL epitope from human oncoprotein (hPEBP4) induces more efficient antitumor responses

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