SYFPEITHI: database for MHC ligands and peptide motifs

Rammensee, Hans‐Georg; Bachmann, Jutta; Emmerich, Niels; Bachor, O. A.; Stevanović, Stefan

doi:10.1007/s002510050595

Cited by 2,105 publications

(2,036 citation statements)

References 22 publications

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“…It has the typical length of MHC class I ligands (9 residues) and contains the characteristic anchor residue leucine at positions 2 and 9. 18 The relatively high affinity of p1028 for HLA-A2 is consistent with the theoretical score in the database for MHC ligands and peptide motifs SYFPEITHI, 19 where this epitope is scored with 28 out of a maximal score for HLA-A2 peptides of 36. For instance, the well-known epitope GILGFVFTL derived from the influenza A matrix protein scores 30.…”

Section: Selection Of Shla-a2-derived Peptidessupporting

confidence: 68%

A novel DNA methyltransferase I–derived peptide eluted from soluble HLA‐A*0201 induces peptide‐specific, tumor‐directed cytotoxic T cells

Berg

Barnea

Admon

et al. 2004

Intl Journal of Cancer

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Key words: soluble HLA; DNMT-1; cancer vaccine; tumor antigen; immunotherapyThe preferred approach for the elimination of tumor cells is to elicit a specific antitumor CTL response that will select tumor cells presenting the appropriate T-cell epitopes. 1-4 Human clinical trials for a variety of malignant diseases showed that T-cell therapy was effective and curative for some individuals. 5,6 A number of TAAs have been identified, mainly melanoma antigens, such as Melan-A and MART-1. Studies were initiated to vaccinate tumor patients against these antigens, and their ability to induce antitumor T-cell immunity has been shown in clinical studies. 7 Many of the recently identified antigens are nonmutated differentiation antigens overexpressed in tumors, e.g., a peptide derived from protein tyrosinase that was shown to successfully induce the attack and lysis of melanoma cells from cancer patients. 8 Several strategies have evolved to identify novel TAAs, e.g., cloning of epitopes recognized by CTLs 9 and SEREX technology, 10 where a patient's antibodies are used to identify tumor antigens from a cDNA expression library made from mRNA of tumor specimens.Conventionally, endogenous peptides have been eluted from affinity-purified HLA, such as HLA-A*0201, followed by analysis and sequencing using HPLC combined with tandem mass spectrometry. 11,12 HLA class I molecules are integral membrane glycoproteins; however, the presence of a soluble form of these molecules was demonstrated decades ago. 13,14 Similar to membrane-bound MHC, sMHC class I molecules bind peptides which are 8 -10 amino acids long, with a few exceptions having a length of 6, 11 and 12 amino acids. 15 Purification of MHC molecules is complicated due to their unavoidable contamination with cell debris and detergents after cell lysis. We recently identified HLA-restricted, tumor-specific antigens presented by the sMHC class I molecule by transfecting human tumor cell lines with truncated genes of HLA-A2. After purification of the secreted sHLA by affinity chromatography, peptides were eluted and sequenced. 15 Novel peptides unique to the sMHC variants were identified and screened for tumor-relevant precursor proteins. Detection of these peptides on sMHC indicates that these peptides are properly processed and displayed on transfected sMHC molecules similarly to those displayed on membrane-bound MHC molecules. Peptides recovered from sHLA molecules form similar patterns to those of membrane-bound HLA and include known MHC peptides. 15 Therefore, the repertoire of MHC peptides recovered from sMHC molecules is a good representation of the naturally processed and displayed peptides of transfected cells. Peptides detected this way should be presented at many copy numbers per cell and are likely to be bound with relatively high affinity to HLA.Use of sHLA as a source of peptides enabled us to identify large numbers of MHC peptides presented by human cancer cells and to screen these for peptides possibly derived from TAAs as candidates for tumor vaccination. 15 ...

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Section: Selection Of Shla-a2-derived Peptidessupporting

confidence: 68%

A novel DNA methyltransferase I–derived peptide eluted from soluble HLA‐A*0201 induces peptide‐specific, tumor‐directed cytotoxic T cells

Berg

Barnea

Admon

et al. 2004

Intl Journal of Cancer

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“…After identification of the two most immunogenic mutated Kras and p53 derived peptide sequences (2 out of the total 19 mutated peptide sequences tested), we next determined possible epitopes that could be processed from the long peptides and presented in the employed HLA context. To identify HLA binding minimal epitopes, the two long peptide sequences were subjected to in silico prediction algorithms of the NetMHC 57,58 and the SYFPEITHI 59 databases. Affinity scores for all overlapping 9-mer, 10-mer and 15-mer small peptides possibly processed from the long peptides and binding to HLA-A*0201 and HLA-DRB1*0101 were predicted and affinity scores for wt and mutated sequences were compared.…”

Section: Resultsmentioning

confidence: 99%

“…Stocks were aliquoted (25 µl, 50 µl) and stored at −20°C. Possible HLA-A*0201 and HLA-DRB1*0101 ligands that might be processed from the long peptides were predicted using the SYFPEITHI 59 and NetMHC 57,58 algorithms. Lists of peptides used can be found in the Supplementary Tables 1, 4 and 4.…”

Section: Methodsmentioning

confidence: 99%

Long-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses

et al. 2018

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Mutated proteins arising from somatic mutations in tumors are promising targets for cancer immunotherapy. They represent true tumor-specific antigens (TSAs) as they are exclusively expressed in tumors, reduce the risk of autoimmunity and are more likely to overcome tolerance compared to wild-type (wt) sequences. Hence, we designed a panel of long peptides (LPs, 28–35 aa) comprising driver gene mutations in TP35 and KRAS frequently found in gastrointestinal tumors to test their combined immunotherapeutic potential. We found increased numbers of T cells responsive against respective mutated and wt peptides in colorectal cancer patients that carry the tested mutations in their tumors than patients with other mutations. Further, active immunization of HLA(-A2/DR1)-humanized mice with mixes of the same mutated LPs yielded simultaneous, polyvalent CD8+/CD4+ T cell responses against the majority of peptides. Peptide-specific T cells possessed a multifunctional cytokine profile with CD4+ T cells showing a TH1-like phenotype. Two mutated peptides (Kras[G12V], p53[R248W]) induced significantly higher T cell responses than corresponding wt sequences and comprised HLA-A2/DR1-restricted mutated epitopes. However, vaccination with the same highly immunogenic LPs strongly increased systemic regulatory T cells (Treg) numbers in a syngeneic sarcoma model over-expressing these mutated protein variants and resulted in accelerated tumor outgrowth. In contrast, tumor outgrowth was delayed when vaccination was directed against tumor-intrinsic Kras/Tp53 mutations of lower immunogenicity. Conclusively, we show that LP vaccination targeting multiple mutated TSAs elicits polyvalent, multifunctional, and mutation-specific effector T cells capable of targeting tumors. However, the success of this therapeutic approach can be hampered by vaccination-induced, TSA-specific Tregs.

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“…The predictions were performed for 8–11‐mer peptides with NetMHC 4.0,18 NetMHC 3.4,19 NetMHCpan 3.0,20 NetMHCpan 2.8,20 NetMHCcons 1.1,21 Consensus,22 PickPocket 1.1,23 SMM,24 SMMPMBEC,25 BIMAS,26 and SYFPEITHI 27. Results of all prediction algorithms were combined.…”

Section: Methodsmentioning

confidence: 99%

A Targeted LC‐MS Strategy for Low‐Abundant HLA Class‐I‐Presented Peptide Detection Identifies Novel Human Papillomavirus T‐Cell Epitopes

et al. 2018

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For rational design of therapeutic vaccines, detailed knowledge about target epitopes that are endogenously processed and truly presented on infected or transformed cells is essential. Many potential target epitopes (viral or mutation‐derived), are presented at low abundance. Therefore, direct detection of these peptides remains a challenge. This study presents a method for the isolation and LC‐MS3‐based targeted detection of low‐abundant human leukocyte antigen (HLA) class‐I‐presented peptides from transformed cells. Human papillomavirus (HPV) was used as a model system, as the HPV oncoproteins E6 and E7 are attractive therapeutic vaccination targets and expressed in all transformed cells, but present at low abundance due to viral immune evasion mechanisms. The presented approach included preselection of target antigen‐derived peptides by in silico predictions and in vitro binding assays. The peptide purification process was tailored to minimize contaminants after immunoprecipitation of HLA‐peptide complexes, while keeping high isolation yields of low‐abundant target peptides. The subsequent targeted LC‐MS3 detection allowed for increased sensitivity, which resulted in successful detection of the known HLA‐A2‐restricted epitope E711–19 and ten additional E7‐derived peptides on the surface of HPV16‐transformed cells. T‐cell reactivity was shown for all the 11 detected peptides in ELISpot assays, which shows that detection by our approach has high predictive value for immunogenicity. The presented strategy is suitable for validating even low‐abundant candidate epitopes to be true immunotherapy targets.

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SYFPEITHI: database for MHC ligands and peptide motifs

Cited by 2,105 publications

References 22 publications

A novel DNA methyltransferase I–derived peptide eluted from soluble HLA‐A*0201 induces peptide‐specific, tumor‐directed cytotoxic T cells

A novel DNA methyltransferase I–derived peptide eluted from soluble HLA‐A*0201 induces peptide‐specific, tumor‐directed cytotoxic T cells

Long-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses

A Targeted LC‐MS Strategy for Low‐Abundant HLA Class‐I‐Presented Peptide Detection Identifies Novel Human Papillomavirus T‐Cell Epitopes

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