Her-2/ neu altered peptide ligand?induced CTL responses: implications for peptides with increased HLA affinity and T-cell-receptor interaction

Dionne, Sara O.; Myers, Cheryl; Smith, Margaret H.; Lake, Douglas F.

doi:10.1007/s00262-003-0439-y

Cited by 9 publications

(9 citation statements)

References 30 publications

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“…Further experiments, including the measurement of binding affinities, need to be carried out to clarify the advantage of this mutated peptide. The usefulness of anchor-modified peptides is still controversial (49)(50)(51)(52) and there are a certain differences in clinical responses among individual anchor-modified peptides. Analysis on immune responses in vivo in clinical trials could give us useful information to solve these questions.…”

Section: Discussionmentioning

confidence: 99%

Identification of secernin 1 as a novel immunotherapy target for gastric cancer using the expression profiles of cDNA microarray

et al. 2006

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Despite the discovery of multiple TAAs, only a limited number is available for clinical application, particularly against epithelial malignancies. In this study we searched for novel TAAs using expression profiles of gastric cancer examined with cDNA microarray, and identified the SCRN1 gene as a candidate. SCRN1 was confirmed to be expressed in five out of seven gastric cancers with semiquantitative RT-PCR. With Northern blot analysis, it was detected abundantly in the testis and ovary, but it was barely detectable in 14 other normal human adult organs. Colony formation assay revealed that its augmented expression is associated with promoted cell growth. As these expression profiles and functional features of SCRN1 appeared to be compatible with the characteristics of the hypothesized ideal TAAs, we examined whether SCRN1 protein contains antigenic epitope peptides restricted to HLA-A*0201. We synthesized the candidate peptides derived from SCRN1, and tried to induce CTLs with each peptide. The CTL clones were successfully induced with a peptide SCRN1-196 (KMDAEHPEL), and they lyzed not only the peptide-pulsed targets but also the tumor cells expressing both SCRN1 and HLA-A*0201 endogenously. These results strongly suggest that SCRN1-196 is an epitope peptide restricted to HLA-A*0201. Furthermore, we synthesized an anchor-modified peptide SCRN1-9 V (KMDAEHPEV), in which leucine at position 9 was substituted for valine to increase the binding affinity to the HLA-A*0201 molecules. The CTL clones induced by SCRN1-9 V also recognized tumor cells expressing its natural SCRN1 protein endogenously. These results strongly suggest that SCRN1 is a novel TAA and these peptides, both native and modified, may be applicable for cancer vaccines to treat gastric cancer. (Cancer Sci 2006; 97: 411-419)

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Section: Discussionmentioning

confidence: 99%

Identification of secernin 1 as a novel immunotherapy target for gastric cancer using the expression profiles of cDNA microarray

et al. 2006

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“…The following HLA-A*0201-binding peptides were used in this study: TRP-2 (SVYDFFVWL), optimized peptide ligand (OPL) 2.1 (FVYD-FFVWL), OPL2.2 (FLYDFFVWL) and OPL2.3 (FLFDFFVWL), hepatitis B core antigen (FLPSDYFPSV, residues [18][19][20][21][22][23][24][25][26][27], and influenza virus matrix peptide (M1: 58-66, GILGFVFTL). Peptides were synthesized using standard fluorenyl-methoxy-carbonyl (FMOC) chemistry and purified by high-performance liquid chromatography to Ͼ90%.…”

Section: Hla-a*0201-binding Synthetic Peptidesmentioning

confidence: 99%

“…Relative affinity assays were performed to determine affinities of OPL for HLA-A*0201 molecules as previously reported [23]. The HBV core antigen (FLPSDYFPSV) was synthesized with a cysteine residue substituted for the tyrosine residue at position 6.…”

Section: Hla-a*0201 Binding Affinity Of Modified Trp-2 Peptidesmentioning

confidence: 99%

“…Based upon the relative affinity results alone, it would be predicted that OPL2.3 would elicit the most CTL compared with CTL raised on the other peptides. However, we have observed in other studies that optimized peptides with the best affinity do not always induce the most active CTL or elicit CTL from the most individuals [23,34]. Therefore, we raised CTL on each peptide and tested their reactivities against wild-type peptides.…”

Section: Relative Affinity Of Opl To Hla-a2mentioning

confidence: 99%

“…Active immunotherapy using optimized tumor-associated antigen epitopes is designed to elicit tumor-specific CTL that can overcome tolerance and initiate a robust T-cell response to an antigen [23,24]. HLA-A2 allele-binding peptides are normally nonamers with P2 and P9 as primary anchor residues [25].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Variation in cytotoxic T-lymphocyte responses to peptides derived from tyrosinase-related protein-2

et al. 2008

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Identification of HLA-Cw6.02 and HLA-Cw7.01 allele-specific binding motifs by screening synthetic peptide libraries

et al. 2004

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Unlike HLA-A and HLA-B, few peptide epitope motifs have been reported for HLA-C molecules. However, a number of cytotoxic T-lymphocyte epitopes derived from tumor antigens that bind to HLA-C molecules have been described. Here we report peptide-binding motifs for both HLA-Cw6.02 and HLA-Cw7.01 molecules. Recombinant human HLA molecules were generated and used to screen combinatorial 9mer peptide libraries. Complexes of HLA molecules properly folded and associated with beta2-microglobulin and peptides were identified using a conformation-specific HLA class I antibody conjugated to alkaline phosphatase. In the presence of substrate, peptide beads can be readily isolated and microsequenced to determine peptide identity. Of the peptides that bound to HLA-Cw6.02 and HLA-Cw7.01, 19 and 18 peptides, respectively, were sequenced, allowing motif identification for each C allele. This is the first report of an HLA-Cw7.01 peptide motif and extends the findings of Falk et al. [(1993) Proc Natl Acad Sci USA 90:12005] for an HLA-Cw6.02 motif. Anchoring amino acids for the HLA-Cw6.02 motif were phenylalanine or tyrosine in position (P)1, arginine in P2, and an aliphatic/aromatic residue at P9. Anchoring residues for HLA-Cw7.01 were positively charged amino acids in P1 and P2. Unlike most other HLA molecules, we were unable to assign P9 an anchoring residue, and we suspect that HLA-Cw7.01 binds peptides in an unconventional manner. Additionally, preferred amino acids were identified for both molecules. Identification of HLA-Cw6.02 and HLA-Cw7.01 peptide-binding motifs makes a significant contribution to the C allele peptide-binding motifs and will allow investigators to predict, design, and test HLA-Cw6.02 and HLA-Cw7.01 engineered peptides for immunotherapy.

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Her-2/ neu altered peptide ligand?induced CTL responses: implications for peptides with increased HLA affinity and T-cell-receptor interaction

Cited by 9 publications

References 30 publications

Identification of secernin 1 as a novel immunotherapy target for gastric cancer using the expression profiles of cDNA microarray

Identification of secernin 1 as a novel immunotherapy target for gastric cancer using the expression profiles of cDNA microarray

Variation in cytotoxic T-lymphocyte responses to peptides derived from tyrosinase-related protein-2

Identification of HLA-Cw6.02 and HLA-Cw7.01 allele-specific binding motifs by screening synthetic peptide libraries

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