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Induction of protective antitumor immunity through attenuation of ERAAP function

Induction of protective antitumor immunity through attenuation of ERAAP function
Induction of protective antitumor immunity through attenuation of ERAAP function
The endoplasmic reticulum aminopeptidase associated with Ag processing, ERAAP, plays an important role in the trimming of antigenic peptides for presentation at the cell surface complexed with MHC class I molecules. Tumors express varying levels of ERAAP, highlighting a possible mechanism of immune-evasion through alteration of the peptide repertoire. Using the CT26 tumor model, we investigated the effects of ERAAP modulation on peptide presentation and the use of ERAAP inhibition as an antitumor therapy. We show that generation of the cross-protective tumor Ag GSW11 in the colorectal carcinoma CT26 is increased when ERAAP expression is reduced. BALB/c mice with reduced ERAAP expression challenged with CT26 induced protective immunity that was mediated by CD8+ T cells. This antitumor immunity also protected mice when rechallenged with wild-type CT26 tumor; strong CD8+ T cell responses to GSW11 were observed, despite its presentation being considerably lower. Furthermore, boosting the tumor immunogenicity through inhibition of ERAAP function with the small molecule inhibitor leucinethiol in vitro, or in established tumors in vivo, abrogated tumor growth and prolonged survival. Thus, our results highlight the promising possibility of using modulation of ERAAP to generate protective antitumor responses as a strategy for cancer immunotherapy.
0022-1767
5839-5846
James, E.
7dc1afb7-d326-4050-89fc-1f4e2a1a19a4
Bailey, I.
e4ade4c4-d5c5-4358-a506-29f797c788f3
Sugiyarto, G.
c7308fe8-ac6d-4c5c-b0ea-ad29a487c013
Elliott, T.
16670fa8-c2f9-477a-91df-7c9e5b453e0e
James, E.
7dc1afb7-d326-4050-89fc-1f4e2a1a19a4
Bailey, I.
e4ade4c4-d5c5-4358-a506-29f797c788f3
Sugiyarto, G.
c7308fe8-ac6d-4c5c-b0ea-ad29a487c013
Elliott, T.
16670fa8-c2f9-477a-91df-7c9e5b453e0e

James, E., Bailey, I., Sugiyarto, G. and Elliott, T. (2013) Induction of protective antitumor immunity through attenuation of ERAAP function Journal of Immunology, 190, (11), pp. 5839-5846. (doi:10.4049/jimmunol.1300220). (PMID:23610143).

Record type: Article

Abstract

The endoplasmic reticulum aminopeptidase associated with Ag processing, ERAAP, plays an important role in the trimming of antigenic peptides for presentation at the cell surface complexed with MHC class I molecules. Tumors express varying levels of ERAAP, highlighting a possible mechanism of immune-evasion through alteration of the peptide repertoire. Using the CT26 tumor model, we investigated the effects of ERAAP modulation on peptide presentation and the use of ERAAP inhibition as an antitumor therapy. We show that generation of the cross-protective tumor Ag GSW11 in the colorectal carcinoma CT26 is increased when ERAAP expression is reduced. BALB/c mice with reduced ERAAP expression challenged with CT26 induced protective immunity that was mediated by CD8+ T cells. This antitumor immunity also protected mice when rechallenged with wild-type CT26 tumor; strong CD8+ T cell responses to GSW11 were observed, despite its presentation being considerably lower. Furthermore, boosting the tumor immunogenicity through inhibition of ERAAP function with the small molecule inhibitor leucinethiol in vitro, or in established tumors in vivo, abrogated tumor growth and prolonged survival. Thus, our results highlight the promising possibility of using modulation of ERAAP to generate protective antitumor responses as a strategy for cancer immunotherapy.

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Published date: 22 April 2013
Organisations: Cancer Sciences

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Local EPrints ID: 351996
URI: http://eprints.soton.ac.uk/id/eprint/351996
ISSN: 0022-1767
PURE UUID: a80fa08b-a7b4-4f4f-9d9a-c6cfc8cccb2e
ORCID for T. Elliott: ORCID iD orcid.org/0000-0003-1097-0222

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Date deposited: 30 Apr 2013 12:03
Last modified: 18 Jul 2017 04:20

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Contributors

Author: E. James
Author: I. Bailey
Author: G. Sugiyarto
Author: T. Elliott ORCID iD

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