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DNA fusion vaccine designs to induce tumor-lytic CD8+ T-cell attack via the immunodominant cysteine-containing epitope of NY-ESO 1

DNA fusion vaccine designs to induce tumor-lytic CD8+ T-cell attack via the immunodominant cysteine-containing epitope of NY-ESO 1
DNA fusion vaccine designs to induce tumor-lytic CD8+ T-cell attack via the immunodominant cysteine-containing epitope of NY-ESO 1
The cancer/testis antigen NY-ESO-1 contains an immunodominant HLA-A2-binding peptide (SLLMWITQC), designated S9C, an attractive target for vaccination against several human cancers. As cysteine contains a reactive ?SH, the oxidation status of exogenous synthetic peptide is uncertain. We have designed tolerance-breaking DNA fusion vaccines incorporating a domain of tetanus toxin fused to tumor-derived peptide sequences (p.DOM-peptide), placed at the C-terminus for optimal immunogenicity. In a "humanized" HLA-A2 preclinical model, p.DOM-S9C primed S9C-specific CD8+ T cells more effectively than adjuvanted synthetic peptide. A DNA vaccine encoding the full NY-ESO-1 sequence alone induced only weak S9C-specific responses, amplified by addition of DOM sequence. The analog peptide (SLLMWITQL) also primed peptide-specific CD8+ T cells, again increased by DNA delivery. Importantly, T cells induced by S9C-encoding DNA vaccines killed tumor cells expressing endogenous NY-ESO-1. Only a fraction of T cells induced by the S9L-encoding DNA vaccines was able to recognize S9C and kill tumor cells. These data indicate that DNA vaccines mimic posttranslational modifications of ?SH-containing peptides expressed by tumor cells. Instability of synthetic peptides and the potential dangers of analog peptides contrast with the ability of DNA vaccines to induce high levels of tumor-lytic peptide-specific CD8+ T cells. These findings encourage clinical exploration of this vaccine strategy to target NY-ESO-1
dna vaccines, cancer testis antigens, tumor peptides, cytotoxic T cells
0020-7136
1400-1407
Campos-Perez, Juan
f7e97282-bda5-4f5f-8272-de4f613aacda
Rice, Jason
d58d4fcd-8dc0-4599-bf96-62323d579227
Escors, David
0cb4a969-f1cc-4ab5-a87f-aeb1f0554865
Collins, Mary
86818e17-4a48-42c9-90e6-eae727b65513
Paterson, Alex
0a9ef773-a7e7-4584-9c3c-db15754c3bd6
Savelyeva, Natalia
804c3e15-d260-4717-9b7c-15c16ba87fc7
Stevenson, Freda K.
ba803747-c0ac-409f-a9c2-b61fde009f8c
Campos-Perez, Juan
f7e97282-bda5-4f5f-8272-de4f613aacda
Rice, Jason
d58d4fcd-8dc0-4599-bf96-62323d579227
Escors, David
0cb4a969-f1cc-4ab5-a87f-aeb1f0554865
Collins, Mary
86818e17-4a48-42c9-90e6-eae727b65513
Paterson, Alex
0a9ef773-a7e7-4584-9c3c-db15754c3bd6
Savelyeva, Natalia
804c3e15-d260-4717-9b7c-15c16ba87fc7
Stevenson, Freda K.
ba803747-c0ac-409f-a9c2-b61fde009f8c

Campos-Perez, Juan, Rice, Jason, Escors, David, Collins, Mary, Paterson, Alex, Savelyeva, Natalia and Stevenson, Freda K. (2015) DNA fusion vaccine designs to induce tumor-lytic CD8+ T-cell attack via the immunodominant cysteine-containing epitope of NY-ESO 1. International Journal of Cancer, 133 (6), 1400-1407. (doi:10.1002/ijc.28156). (PMID:23494538)

Record type: Article

Abstract

The cancer/testis antigen NY-ESO-1 contains an immunodominant HLA-A2-binding peptide (SLLMWITQC), designated S9C, an attractive target for vaccination against several human cancers. As cysteine contains a reactive ?SH, the oxidation status of exogenous synthetic peptide is uncertain. We have designed tolerance-breaking DNA fusion vaccines incorporating a domain of tetanus toxin fused to tumor-derived peptide sequences (p.DOM-peptide), placed at the C-terminus for optimal immunogenicity. In a "humanized" HLA-A2 preclinical model, p.DOM-S9C primed S9C-specific CD8+ T cells more effectively than adjuvanted synthetic peptide. A DNA vaccine encoding the full NY-ESO-1 sequence alone induced only weak S9C-specific responses, amplified by addition of DOM sequence. The analog peptide (SLLMWITQL) also primed peptide-specific CD8+ T cells, again increased by DNA delivery. Importantly, T cells induced by S9C-encoding DNA vaccines killed tumor cells expressing endogenous NY-ESO-1. Only a fraction of T cells induced by the S9L-encoding DNA vaccines was able to recognize S9C and kill tumor cells. These data indicate that DNA vaccines mimic posttranslational modifications of ?SH-containing peptides expressed by tumor cells. Instability of synthetic peptides and the potential dangers of analog peptides contrast with the ability of DNA vaccines to induce high levels of tumor-lytic peptide-specific CD8+ T cells. These findings encourage clinical exploration of this vaccine strategy to target NY-ESO-1

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More information

e-pub ahead of print date: 11 April 2013
Published date: 15 September 2015
Keywords: dna vaccines, cancer testis antigens, tumor peptides, cytotoxic T cells
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 352141
URI: http://eprints.soton.ac.uk/id/eprint/352141
ISSN: 0020-7136
PURE UUID: d764327b-830c-4e4c-86fb-e17085a2adfe
ORCID for Freda K. Stevenson: ORCID iD orcid.org/0000-0002-0933-5021

Catalogue record

Date deposited: 07 May 2013 10:58
Last modified: 20 Jul 2019 01:16

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