A general strategy to enhance immunogenicity of low-affinity HLA-A2.1-associated peptides: implication in the identification of cryptic tumor epitopes

Tourdot, Sophie; Scardino, Antonio; Saloustrou, Eleanna; Gross, David-Alexandre; Pascolo, Steve; Cordopatis, P; Lemonnier, François; Kosmatopoulos, Kostas

doi:10.1002/1521-4141(2000012)30:12<3411::aid-immu3411>3.0.co;2-r

Cited by 123 publications

(116 citation statements)

References 31 publications

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“…Four previously described HER-2/neu peptides with low affinity for HLA-A*0201 (neu 391 , neu 402 , neu 466 , and neu 650 ) (18,29) were used in this study. Two hTERT peptides predicted by the Bioinformatics and Molecular Analysis Section algorithm (32) to have low HLA-binding affinity were also included.…”

Section: Low Affinity Her-2/neu and Htert Peptidesmentioning

confidence: 99%

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HER-2/neuand hTERT Cryptic Epitopes as Novel Targets for Broad Spectrum Tumor Immunotherapy

Scardino

Gross

Alves

et al. 2002

The Journal of Immunology

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118

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Tolerance to tumor-nonmutated self proteins represents a major obstacle for successful cancer immunotherapy. Since this tolerance primarily concerns dominant epitopes, we hypothesized that targeting cryptic epitopes that have a low affinity for HLA could be an efficient strategy to breach the tolerance to tumor Ags. Using the P1Y heteroclitic peptide approach, we identified low affinity cryptic HLA-A*0201-restricted epitopes derived from two widely expressed tumor Ags, HER-2/neu and hTERT. The P1Y variants of four HER-2/neu (neu391, neu402, neu466, neu650)- and two hTERT (hTERT572 and hTERT988)-derived low affinity peptides exhibited strong affinity for HLA-A*0201 and stimulated specific CTL from healthy donor PBMCs. These CTL specifically recognized HER-2/neu- and hTERT-expressing tumor cells of various histological origins. In vivo studies showed that HLA-A*0201 transgenic HHD mice vaccinated with the P1Y variant peptides generated CTL that specifically lysed Ag-expressing tumor cells, thus recognizing the cognate endogenous Ags. These results suggest that heteroclitic variants of low affinity, cryptic epitopes of widely expressed tumor Ags may serve as valid tools for tumor immunotherapy.

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Section: Low Affinity Her-2/neu and Htert Peptidesmentioning

confidence: 99%

“…To generate CTL against low affinity peptides, we used the P1Y heteroclitic peptide approach we described previously (29). It consists of substituting the amino acid at position 1 with a tyrosine.…”

Section: Generation Of Ctl Against Low Affinity Peptidesmentioning

confidence: 99%

HER-2/neuand hTERT Cryptic Epitopes as Novel Targets for Broad Spectrum Tumor Immunotherapy

Scardino

Gross

Alves

et al. 2002

The Journal of Immunology

Self Cite

118

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“…Previous studies have shown that modification of the secondary anchor motif at position one by an aromatic amino acid, tyrosine (Y), substitution increases the binding and affinity of the peptides. 31,32 After this alteration, the computer algorithm predicted half-lives up to 70 times that of the native peptide sequence for the six peptides ( Table 1). The other three peptides derived from the prediction of binding to HLA-0201 molecules were improved by a single acid substitution introduced at HLA-A0201 primary preferred residues, two of them by a leucine substitution at position two and one by valine substitutions at position nine.…”

Section: Resultsmentioning

confidence: 99%

Improved human T-cell responses against synthetic HLA-0201 analog peptides derived from the WT1 oncoprotein

et al. 2006

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Wilms tumor protein 1 (WT1) is a transcription factor overexpressed in several types of leukemia and solid tumors. For this reason, WT1 is an attractive target for immunotherapy. Four peptide nonamers from WT1 have been identified by others to generate a WT1-specific cytotoxic response in the context of human leukocyte antigen (HLA)-A0201 and A2402. However, as WT1 is a self-antigen, breaking tolerance is a potential obstacle to vaccination. Here, we use a strategy to circumvent tolerance by designing synthetic immunogenic analog peptides that could crossreact to the native peptides (a heteroclitic response). A number of synthetic peptides derived from nonamer sequences of the WT1 protein were designed in which single amino-acid substitutions were introduced at HLA-A0201 major histocompatibility complex (MHC)-binding positions. Several of new peptides could stabilize MHC class I A0201 molecules better than native sequences. Some analogs were also able to elicit WT1-specific T-cell recognition and cytotoxic T-cell lymphocytes more effectively than native sequences. Importantly, T cells stimulated with the new analogs crossreacted with the native WT1 peptide sequence and were able to kill HLA-matched chronic myeloid leukemia cell lines. In conclusion, analog heteroclitic WT1 peptides with increased immunogenicity can be synthesized and are potential cancer vaccine candidates.

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“…In this respect, modification of native peptides in solid tumours, leukaemia, or lymphomas led to peptides with increased immunogenicity against tumour cells [41][42][43][44][45]. On the basis of these findings, one would think that our immune system has failed to eliminate tumours not because tumour antigens were absent, but rather because appropriate lymphocytes were not activated to a threshold required for tumour rejection.…”

Section: Overcoming Immune Tolerance To Tumour Antigensmentioning

confidence: 99%

Does our Current Understanding of Immune Tolerance, Autoimmunity, and Immunosuppressive Mechanisms Facilitate the Design of Efficient Cancer Vaccines?

Sioud

2009

Scand J Immunol

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The therapeutic use of the immune system to attack cancer cells has been a longstanding vision among tumour immunologists. However, most human tumours are poorly immunogenic and are able to invade the host immune system. Although these obstacles are clearly critical to cancer vaccine development, the induction of a strong anti‐tumour immune response may rely on the activation of high affinity T cells through a molecular mimicry mechanism which involves cross‐reactive recognition of foreign antigens mimicking the structure of tumour proteins. Taking into account the disparity in HLA molecules needed to present shared antigens; in late 1990s Stauss et al. described the possibility of generating allorestricted high affinity cytotoxic T cells against synthetic self‐peptides bound to non‐self‐MHC molecules. In addition to the strategies indicated above, the inhibition of the immunosuppressive mechanisms associated with tumour invasion of the immune system using RNA interference also offers a new approach to vaccine design. This review highlights the problem of immune tolerance, the induction of autoreactive T cells, and describes strategies to enhance tumour immunity.

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A general strategy to enhance immunogenicity of low-affinity HLA-A2.1-associated peptides: implication in the identification of cryptic tumor epitopes

Cited by 123 publications

References 31 publications

HER-2/neuand hTERT Cryptic Epitopes as Novel Targets for Broad Spectrum Tumor Immunotherapy

HER-2/neuand hTERT Cryptic Epitopes as Novel Targets for Broad Spectrum Tumor Immunotherapy

Improved human T-cell responses against synthetic HLA-0201 analog peptides derived from the WT1 oncoprotein

Does our Current Understanding of Immune Tolerance, Autoimmunity, and Immunosuppressive Mechanisms Facilitate the Design of Efficient Cancer Vaccines?

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