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An analogue peptide from the Cancer/Testis antigen PASD1 induces CD8+ T cell responses against naturally processed peptide

An analogue peptide from the Cancer/Testis antigen PASD1 induces CD8+ T cell responses against naturally processed peptide
An analogue peptide from the Cancer/Testis antigen PASD1 induces CD8+ T cell responses against naturally processed peptide
We have previously identified the novel Cancer/Testis antigen PASD1 by immunoscreening a testis library with pooled acute myeloid leukemia (AML) patient sera. To develop a cytotoxic T lymphocyte (CTL)-inducing vaccine, we have now investigated the carboxy-terminal region, known to contain serological determinants, for MHC class I (HLA-A?0201)-binding peptides. Algorithm-selected natural peptides failed to show detectable HLA-A?0201 binding in T2 assays. However, anchor-modified analogue peptides showed enhanced binding, with decreased off-rates. Analogue peptide-loaded antigen-presenting cells (APCs) induced IFN-? production by T cells from normal donors and patients. In addition, peptide-specific T cells could be expanded from cancer patients by stimulation with the PASD1 analogue peptide Pa14. For clinical application, a DNA fusion gene vaccine encoding Pa14 was designed and tested in "humanized" mice. Splenocytes from vaccinated mice showed in vitro cytotoxicity against tumour cells, either exogenously loaded with the corresponding wild-type peptide (Pw8) or expressing endogenously processed PASD1 protein. We show for the first time that a DNA vaccine encoding an altered PASD1 epitope can induce CTLs to target the natural peptide expressed by human tumour cells.

PASD1, immunotherapy, acute myeloid leukemia, DNA vaccine, analogue peptide
1424-9634
Hardwick, Nicola
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Buchan, Sarah L.
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Ingram, Wendy
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Khan, Ghazala
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Vittes, Gisella E.
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Rice, Jason
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Pulford, Karen
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Mufti, Ghulam
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Stevenson, Freda
ba803747-c0ac-409f-a9c2-b61fde009f8c
Guinn, Barbara-ann
728d28c9-a23d-413a-ba1d-4531005705d7
Hardwick, Nicola
1d245b15-d892-47f9-aa6d-5cb05d23e6b8
Buchan, Sarah L.
9ade187d-f127-45de-ad90-9d544d64718a
Ingram, Wendy
852f9de8-07c4-4b3b-b70a-60b81e162561
Khan, Ghazala
116581c0-3dde-4b90-89ff-470016517693
Vittes, Gisella E.
0421ca22-87a5-4995-a18a-c4da932838b5
Rice, Jason
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Pulford, Karen
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Mufti, Ghulam
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Stevenson, Freda
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Guinn, Barbara-ann
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Hardwick, Nicola, Buchan, Sarah L., Ingram, Wendy, Khan, Ghazala, Vittes, Gisella E., Rice, Jason, Pulford, Karen, Mufti, Ghulam, Stevenson, Freda and Guinn, Barbara-ann (2013) An analogue peptide from the Cancer/Testis antigen PASD1 induces CD8+ T cell responses against naturally processed peptide. Cancer Immunity, 13 (16). (PMID:23882161)

Record type: Article

Abstract

We have previously identified the novel Cancer/Testis antigen PASD1 by immunoscreening a testis library with pooled acute myeloid leukemia (AML) patient sera. To develop a cytotoxic T lymphocyte (CTL)-inducing vaccine, we have now investigated the carboxy-terminal region, known to contain serological determinants, for MHC class I (HLA-A?0201)-binding peptides. Algorithm-selected natural peptides failed to show detectable HLA-A?0201 binding in T2 assays. However, anchor-modified analogue peptides showed enhanced binding, with decreased off-rates. Analogue peptide-loaded antigen-presenting cells (APCs) induced IFN-? production by T cells from normal donors and patients. In addition, peptide-specific T cells could be expanded from cancer patients by stimulation with the PASD1 analogue peptide Pa14. For clinical application, a DNA fusion gene vaccine encoding Pa14 was designed and tested in "humanized" mice. Splenocytes from vaccinated mice showed in vitro cytotoxicity against tumour cells, either exogenously loaded with the corresponding wild-type peptide (Pw8) or expressing endogenously processed PASD1 protein. We show for the first time that a DNA vaccine encoding an altered PASD1 epitope can induce CTLs to target the natural peptide expressed by human tumour cells.

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e-pub ahead of print date: 15 July 2013
Keywords: PASD1, immunotherapy, acute myeloid leukemia, DNA vaccine, analogue peptide
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 357168
URI: http://eprints.soton.ac.uk/id/eprint/357168
ISSN: 1424-9634
PURE UUID: be8309f9-4824-4faf-b735-e8529b29b287
ORCID for Freda Stevenson: ORCID iD orcid.org/0000-0002-0933-5021

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Date deposited: 03 Oct 2013 13:50
Last modified: 15 Mar 2024 02:53

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Contributors

Author: Nicola Hardwick
Author: Sarah L. Buchan
Author: Wendy Ingram
Author: Ghazala Khan
Author: Gisella E. Vittes
Author: Jason Rice
Author: Karen Pulford
Author: Ghulam Mufti
Author: Freda Stevenson ORCID iD
Author: Barbara-ann Guinn

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