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Effect of ERAP1 modulation on induction of protective anti-tumour immunity

Effect of ERAP1 modulation on induction of protective anti-tumour immunity
Effect of ERAP1 modulation on induction of protective anti-tumour immunity
ERAP1 trimming of antigenic peptides has an important role in anti-cancer immune responses, by generating optimal peptides for MHC-I loading and presentation to CD8+ T cells. Previous studies reveal that ERAP1 overexpression in colon carcinomas results in over-trimming and destruction of protective cancer-related antigens, such as GSW11. Moreover, ERAP1 knockdown by RNAi induces effective anticancer immune reactions against CT26 colon carcinoma cells in vivo and stimulates an immunological memory. In humans ERAP1 is highly polymorphic and different allotypes with distinct trimming characteristics are associated with pathologic conditions. We aim to investigate if ERAP1 knock-out increases the immunogenicity of MC38 cells in vivo and whether the trimming efficacies of different human ERAP1 allotypes alters anti-tumour responses.

We established an ERAP1 knock-out MC38 colon carcinoma cell line using a CRISPR-Cas9 approach. Different ERAP1 haplotypes were introduced into ERAP1 knock-out cells using MSCV viral vector. The absence of ERAP1 reduced the stability of H2-Kb but not H2-Db complexes, with ERAP1 re-expression recovering H2-Kb stability. In vivo experiments conducted on syngeneic mice injected with wild-type or ERAP1 knock-out MC38 cells indicate that the absence of ERAP1 expression results in slower tumour growth and increased survival. The analysis of tumour immune infiltrate identified a differential abundance of some immune cell populations correlating with the ERAP1 trimming phenotype of tumour cells injected. Interestingly, mice surviving the first challenge with ERAP1KO cells were also protected from rechallenged with wild-type MC38 cells. These data suggest that ERAP1 knock-out increases MC38 cells' immunogenicity in vivo and leads to the establishment of antitumour immunological memory.
ERAP1, colon carcinoma, immunotherapy
University of Southampton
Guglietta, Dario Vinicio
c01b7a28-5f7f-4e5e-a22c-01170d0bc8bb
Guglietta, Dario Vinicio
c01b7a28-5f7f-4e5e-a22c-01170d0bc8bb
James, Edd
7dc1afb7-d326-4050-89fc-1f4e2a1a19a4
Reeves, Emma
bd61ff0c-6555-47fd-884f-74dc6105e846

Guglietta, Dario Vinicio (2025) Effect of ERAP1 modulation on induction of protective anti-tumour immunity. University of Southampton, Doctoral Thesis, 143pp.

Record type: Thesis (Doctoral)

Abstract

ERAP1 trimming of antigenic peptides has an important role in anti-cancer immune responses, by generating optimal peptides for MHC-I loading and presentation to CD8+ T cells. Previous studies reveal that ERAP1 overexpression in colon carcinomas results in over-trimming and destruction of protective cancer-related antigens, such as GSW11. Moreover, ERAP1 knockdown by RNAi induces effective anticancer immune reactions against CT26 colon carcinoma cells in vivo and stimulates an immunological memory. In humans ERAP1 is highly polymorphic and different allotypes with distinct trimming characteristics are associated with pathologic conditions. We aim to investigate if ERAP1 knock-out increases the immunogenicity of MC38 cells in vivo and whether the trimming efficacies of different human ERAP1 allotypes alters anti-tumour responses.

We established an ERAP1 knock-out MC38 colon carcinoma cell line using a CRISPR-Cas9 approach. Different ERAP1 haplotypes were introduced into ERAP1 knock-out cells using MSCV viral vector. The absence of ERAP1 reduced the stability of H2-Kb but not H2-Db complexes, with ERAP1 re-expression recovering H2-Kb stability. In vivo experiments conducted on syngeneic mice injected with wild-type or ERAP1 knock-out MC38 cells indicate that the absence of ERAP1 expression results in slower tumour growth and increased survival. The analysis of tumour immune infiltrate identified a differential abundance of some immune cell populations correlating with the ERAP1 trimming phenotype of tumour cells injected. Interestingly, mice surviving the first challenge with ERAP1KO cells were also protected from rechallenged with wild-type MC38 cells. These data suggest that ERAP1 knock-out increases MC38 cells' immunogenicity in vivo and leads to the establishment of antitumour immunological memory.

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Dario Guglietta PhD thesis FINAL A-3a - Version of Record
Restricted to Repository staff only until 31 December 2025.
Available under License University of Southampton Thesis Licence.
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More information

Published date: 25 April 2025
Keywords: ERAP1, colon carcinoma, immunotherapy

Identifiers

Local EPrints ID: 501863
URI: http://eprints.soton.ac.uk/id/eprint/501863
PURE UUID: f6facdad-42de-4eba-a162-5e712216fe17
ORCID for Edd James: ORCID iD orcid.org/0000-0001-8638-7928

Catalogue record

Date deposited: 11 Jun 2025 16:48
Last modified: 11 Sep 2025 02:15

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Contributors

Author: Dario Vinicio Guglietta
Thesis advisor: Edd James ORCID iD
Thesis advisor: Emma Reeves

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