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HPV epitope processing differences correlate with ERAP1 allotype and extent of CD8+ T cell tumor infiltration in OPSCC

HPV epitope processing differences correlate with ERAP1 allotype and extent of CD8+ T cell tumor infiltration in OPSCC
HPV epitope processing differences correlate with ERAP1 allotype and extent of CD8+ T cell tumor infiltration in OPSCC
Presence of tumor-infiltrating lymphocytes (TIL) predicts survival in many cancer types. In HPV-driven cancers, cervical and oropharyngeal squamous cell carcinomas (CSCC and OPSCC, respectively), numbers of infiltrating T cells, particularly CD8+ T cells, and presentation of HPV E6/E7 epitopes are associated with improved prognosis. Endoplasmic reticulum aminopeptidase 1 (ERAP1) regulates the presented peptide repertoire, trimming peptide precursors prior to MHC I loading. ERAP1 is polymorphic, and allotypic variation of ERAP1 enzyme activity has an impact on the presented peptide repertoire. Individual SNPs are associated with incidence and outcome in a number of diseases, including CSCC. Here, we highlight the requirement for ERAP1 in the generation of HPV E6/E7 epitopes and show that the functional activity of ERAP1 allotype combinations identified in OPSCC correlate with tumor-infiltrating CD8+ T-cell (CD8)/TIL (CD8/TIL) status of the tumor. Functional analyses revealed that ERAP1 allotype combinations associated with CD8/TILlow tumors have a reduced capacity to generate both a model antigen SIINFEHL and the HPV-16 E782-90 epitope LLMGTLGIV from N-terminally extended precursor peptides. In contrast, ERAP1 allotypes from CD8/TILhigh tumors generated the epitopes efficiently. These data reveal that ERAP1 function correlates with CD8/TIL numbers and, by implication, prognosis, suggesting that the presentation of HPV-16 epitopes at the cell surface, resulting in an anti-HPV T-cell response, may depend on the ERAP1 allotype combinations expressed within an individual.
2326-6066
1202-1213
Reeves, Emma
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Wood, Oliver
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Ottensmeier, Christian
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King, Emma
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Thomas, Gareth
2ff54aa9-a766-416b-91ee-cf1c5be74106
Elliott, Timothy
16670fa8-c2f9-477a-91df-7c9e5b453e0e
James, Edward
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Reeves, Emma
bd61ff0c-6555-47fd-884f-74dc6105e846
Wood, Oliver
dad2f90c-70a5-44a0-914a-52809b75d1c6
Ottensmeier, Christian
42b8a398-baac-4843-a3d6-056225675797
King, Emma
d85e0e8f-7295-4912-9052-646a790d99db
Thomas, Gareth
2ff54aa9-a766-416b-91ee-cf1c5be74106
Elliott, Timothy
16670fa8-c2f9-477a-91df-7c9e5b453e0e
James, Edward
7dc1afb7-d326-4050-89fc-1f4e2a1a19a4

Reeves, Emma, Wood, Oliver, Ottensmeier, Christian, King, Emma, Thomas, Gareth, Elliott, Timothy and James, Edward (2019) HPV epitope processing differences correlate with ERAP1 allotype and extent of CD8+ T cell tumor infiltration in OPSCC. Cancer Immunology Research, 7 (7), 1202-1213. (doi:10.1158/2326-6066.CIR-18-0498).

Record type: Article

Abstract

Presence of tumor-infiltrating lymphocytes (TIL) predicts survival in many cancer types. In HPV-driven cancers, cervical and oropharyngeal squamous cell carcinomas (CSCC and OPSCC, respectively), numbers of infiltrating T cells, particularly CD8+ T cells, and presentation of HPV E6/E7 epitopes are associated with improved prognosis. Endoplasmic reticulum aminopeptidase 1 (ERAP1) regulates the presented peptide repertoire, trimming peptide precursors prior to MHC I loading. ERAP1 is polymorphic, and allotypic variation of ERAP1 enzyme activity has an impact on the presented peptide repertoire. Individual SNPs are associated with incidence and outcome in a number of diseases, including CSCC. Here, we highlight the requirement for ERAP1 in the generation of HPV E6/E7 epitopes and show that the functional activity of ERAP1 allotype combinations identified in OPSCC correlate with tumor-infiltrating CD8+ T-cell (CD8)/TIL (CD8/TIL) status of the tumor. Functional analyses revealed that ERAP1 allotype combinations associated with CD8/TILlow tumors have a reduced capacity to generate both a model antigen SIINFEHL and the HPV-16 E782-90 epitope LLMGTLGIV from N-terminally extended precursor peptides. In contrast, ERAP1 allotypes from CD8/TILhigh tumors generated the epitopes efficiently. These data reveal that ERAP1 function correlates with CD8/TIL numbers and, by implication, prognosis, suggesting that the presentation of HPV-16 epitopes at the cell surface, resulting in an anti-HPV T-cell response, may depend on the ERAP1 allotype combinations expressed within an individual.

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2326-6066.CIR-18-0498.full - Accepted Manuscript
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Accepted/In Press date: 9 May 2019
e-pub ahead of print date: 31 May 2019
Published date: July 2019

Identifiers

Local EPrints ID: 431582
URI: http://eprints.soton.ac.uk/id/eprint/431582
ISSN: 2326-6066
PURE UUID: 98953071-8f7f-41a3-9cc9-17c57401833d
ORCID for Timothy Elliott: ORCID iD orcid.org/0000-0003-1097-0222
ORCID for Edward James: ORCID iD orcid.org/0000-0001-8638-7928

Catalogue record

Date deposited: 10 Jun 2019 16:30
Last modified: 26 Nov 2021 05:33

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Contributors

Author: Emma Reeves
Author: Oliver Wood
Author: Emma King
Author: Gareth Thomas
Author: Timothy Elliott ORCID iD
Author: Edward James ORCID iD

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