Enhanced Antigen-Specific Antitumor Immunity with Altered Peptide Ligands that Stabilize the MHC-Peptide-TCR Complex

Slansky, Jill E.; Rattis, Frédérique Marie; Boyd, Lisa F.; Fahmy, Tarek M.; Jaffee, Elizabeth M.; Schneck, Jonathan P.; Margulies, David H.; Pardoll, Drew M.

doi:10.1016/s1074-7613(00)00052-2

Cited by 288 publications

(303 citation statements)

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“…We presumed that the improved immunogenicity of W5F might be partly due to better engagement by the TCR, since the PMFScore value predicted increased interaction between the TCR and W5F-HLA-A2 complex. As reported by Slansky and colleagues, the enhanced immunogenicity of an APL of a gp70 tumor epitope correlated with an enhanced binding affinity between the TCR with the pMHC complex compared with the WT epitope [9]. In addition, the result from the HLA presentation study showed that the conservative substitutions did not cause any alteration in MHC binding.…”

Section: Discussionsupporting

confidence: 53%

“…Similarly, several APL with TCR contact residues mutation were originally identified using single specific T-cell clone in vitro, and these APL were much more efficient at expanding and activating the WT specific T-cells pool besides the original T-cell clone [9,14]. These studies and www.eji-journal.eu our findings strongly suggest that a large T-cell repertoire exists in vivo, whose TCR displays common structural features and reactivity patterns to original T-cell clone.…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, several APL with TCR contact residues mutation were originally identified using single specific T-cell clone in vitro, and these APL were much more efficient at expanding and activating the WT specific T-cells pool besides the original T-cell clone [9,14]. These studies and Mice were sacrificed 11 days after immunization, splenocytes isolated and cultured for 5 days with 10 mg/mL of autologous splenocytes loaded with either WT peptide in the presence/absence of an anti-HLA-A2 antibody derived from BB7.2 or an irrelevant peptide (HIV pol476-484 ).…”

Section: Discussionmentioning

confidence: 99%

“…APL with increased pMHC complex affinity for the TCR molecule, which are designed by modifications at the TCR contact sites rather than the MHC anchor residues, have unexpected potency to induce stronger T-cell responses and may even covert cross-reactive T cells from a tolerance state [8][9][10]. According to the structure of the TCR/pMHC complex established by X-ray crystallography, recognition of an epitope by T cells is controlled by a few exposed TCR contact residues within the peptide [11].…”

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confidence: 99%

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Rational optimization of tumor epitopes using in silico analysis‐assisted substitution of TCR contact residues

et al. 2009

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Altered peptide ligands with increased affinity of the peptide-MHC complex for the TCR provide an alternative strategy to natural T-cell epitopes for cancer immunotherapy, as they can recruit and stimulate stronger T-cell repertoires. However, it remains unclear how alterations of the TCR contact residues improve the interaction between the peptide-MHC complex and the TCR molecule. In this study, we introduced a molecular simulation strategy to optimize a tumor immunodominant epitope NY-ESO-1 157-165 by the substitution of the potential TCR contact residues. We correlated molecule simulation with T-cell activation capacity assay and detected the effect of modifications of TCR contact residues on T-cell recognition. An agonist peptide W5F with substitution at Trp5 with Phe was identified and it exhibits a stronger ability to induce a cross-reactive CTL response with the WT peptide. Additionally, the W5F-induced CTL could be maintained with the WT peptide and possess higher capacity in lysing native NY-ESO-1-expressing tumor cells. These results provide important insights into the enhanced immunogenicity of epitopes through substitution at the TCR contact sites and revealed a novel molecular simulation approach for rational therapeutic peptide vaccine design.Key words: Cancer immunotherapy . Epitope . Molecular simulation . TCR contact residue IntroductionInduction of antigen-specific CTL by therapeutic peptide vaccination is a promising approach for cancer immunotherapy [1]. The specific cellular immune response starts from recognition by TCR of an immunogenic epitope presented in the context of the class I MHC molecules. Thus, modulation of CTL response by manipulating T-cell epitopes is a particularly attractive approach for cancer immunotherapy, because peptides from cancer cells are usually poorly immunogenic and often induce immune-tolerance [2,3]. Vaccination with altered peptide ligands (APL), which can be generated by appropriate amino acid substitutions at certain T-cell epitopes, has become an attractive strategy to enhance specic T-cell responses to tumors. This strategy can be achieved by two general approaches: (i) by increasing the affinity between the epitope and the MHC through substitution in the MHC anchor residues or (ii) by enhancing the interactions between the TCR and peptide-MHC (pMHC) complex through alteration at the TCR contact residues [4,5].Although APL with altered MHC contact residues can efficiently activate tumor-specific T cells in vitro, vaccination with this kind of APL has generally failed to elicit an effective anti-tumor CTL response 2248that can lead to clinical tumor regression [6,7]. APL with increased pMHC complex affinity for the TCR molecule, which are designed by modifications at the TCR contact sites rather than the MHC anchor residues, have unexpected potency to induce stronger T-cell responses and may even covert cross-reactive T cells from a tolerance state [8][9][10]. According to the structure of the TCR/pMHC complex established by X-ray crystallography, recogni...

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Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

“…Similarly, several APL with TCR contact residues mutation were originally identified using single specific T-cell clone in vitro, and these APL were much more efficient at expanding and activating the WT specific T-cells pool besides the original T-cell clone [9,14]. These studies and Mice were sacrificed 11 days after immunization, splenocytes isolated and cultured for 5 days with 10 mg/mL of autologous splenocytes loaded with either WT peptide in the presence/absence of an anti-HLA-A2 antibody derived from BB7.2 or an irrelevant peptide (HIV pol476-484 ).…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Rational optimization of tumor epitopes using in silico analysis‐assisted substitution of TCR contact residues

et al. 2009

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“…It is reported that CTLs induced by in vitro sensitization using the modified peptide exhibited better recognition of the native peptide compared with CTLs raised with the native peptide (82). Substitutions of amino acids of a peptide epitope, for example, can greatly increase the binding affinity without interfering with the peptide recognition (83)(84)(85)(86). Most of the immunogenic melanoma and melanocyte differentiation antigen peptides have a moderate or relatively low affinity for the HLAA*0201 molecule, in contrast to viral peptides that have high binding affinity for their corresponding MHC-I (87-90).…”

Section: Modification Of Peptidesmentioning

confidence: 99%

Manipulation of MHC-I/TCR Interaction for Immune Therapy

Liu

Gao

2008

Cell Mol Immunol

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Research Advances in Pemphigus

Anhalt

Díaz²

2001

JAMA

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Pemphigus is an autoimmune disorder, known to be caused by autoantibodies directed against critical adhesion molecules of squamous epithelial cells, the desmogleins. These autoantibodies induce blistering of skin and mucosal surfaces and lead to severe morbidity and, potentially, death. Key factors include associated major histocompatibility complex class II genes, the structure of the desmoglein antigens, and the role of autoantibody in impairing cellular adhesion. This article discusses the precise structure of the major histocompatibility complex class II gene-peptide-T-cell receptor complex involved and of the environmental and genetic factors that induce autoimmunity against desmoglein 1. Discovery of antigen-specific immunotherapy and insight into environmental factors that initiate autoimmunity in genetically susceptible individuals are needed.

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Enhanced Antigen-Specific Antitumor Immunity with Altered Peptide Ligands that Stabilize the MHC-Peptide-TCR Complex

Cited by 288 publications

References 57 publications

Rational optimization of tumor epitopes using in silico analysis‐assisted substitution of TCR contact residues

Rational optimization of tumor epitopes using in silico analysis‐assisted substitution of TCR contact residues

Manipulation of MHC-I/TCR Interaction for Immune Therapy

Research Advances in Pemphigus

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