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

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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ORCID for Edd James: orcid.org/0000-0001-8638-7928

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