{"doi":"10.1136/jitc-2020-sitc2020.0446","title":"446 Immunopeptidome changes mediated by a novel ERAP1 inhibitor leads to tumor growth inhibition","abstract":"<h3>Background</h3> Clinical data demonstrates increased antigen presentation diversity is a key factor in determining response rates to checkpoint inhibitors.<sup>1</sup> In addition to tumour mutational burden/microsatellite instability, increased HLA heterozygosity and HLA evolutionary diversity are non-overlapping factors recently identified to further diversify the immunopeptidome and improve clinical response to checkpoint therapies.<sup>2 3</sup> Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an enzyme that trims peptides loaded into classical and nonclassical class I MHC molecules.<sup>4 5</sup> Ablation of mouse ERAAP modifies the immunopeptidome, resulting in improved immunogenicity, generation of CD8 T cell responses and tumor growth inhibition.<sup>6 7</sup> Recently identified selective small molecules potently inhibit ERAP1 across key species and haplotypes.<sup>8</sup> We report the further profiling of lead candidate ERAP1 inhibitors in human primary T cell in vitro assays and in vivo tumor models in mice. <h3>Methods</h3> Human cancer cell lines treated with ERAP1 inhibitors in vitro or in vivo in xenograft mouse models were assessed by immunopeptidomics<sup>9</sup> to profile peptide repertoire changes. Novel or upregulated peptides were also tested in human immunogenicity assays. FACS analysis of T cells stimulated with Tyrosinase mRNA transfected human dendritic cells ± ERAP1 inhibition was to assess T cell repertoire changes. ERAP1 inhibitor and anti PD-1 mAb combination was assessed in syngeneic mouse tumor models to investigate tumour growth inhibition and PD end-points (e.g. IHC). <h3>Results</h3> Analysis of human cervical, lung, colorectal and melanoma cell lines carrying distinct HLA haplotypes demonstrates a consistent and profound effect of ERAP1 inhibition on the immunopeptidome. Novel and upregulated cancer associated antigens identified in association with multiple different HLA-A and B alleles stimulate IFNγ production in primary naïve human T cell immunogenicity assays. The impact of ERAP1 inhibition on the T cell repertoire to the melanoma antigen tyrosinase is ongoing. The combination of ERAP1 inhibitor and anti PD-1 mAb led to significant tumor growth inhibition in the CT26 syngeneic mouse tumor model that correlated with increased infiltration of T cells to the tumor. Further PD end-points to be analysed include immune gene array and TCR Vbeta repertoire. <h3>Conclusions</h3> Grey Wolf ERAP1 inhibitors significantly modify the immunopeptidome both in vitro and in vivo across a broad range of HLA and tumor types. Combination of these inhibitors with anti PD-1 leads to significant T cell infiltration and tumor growth inhibition. Thus, ERAP1 mediated modulation of the immunopeptidome has the potential to drive anti tumor T cell responses and be a transformative immunotherapy. <h3>References</h3> Rizvi N, Hellmann MD, Snyder A, et al. Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer. <i>Science</i>. 2015;348(6230):124–128. Chowell D, Morris LGT, Grigg CM, et al. Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy. <i>Science</i> 2018;359 (6375):582–587. Chowell D, Krishna C, Pierini F, et al. Evolutionary divergence of HLA class I genotype impacts efficacy of cancer immunotherapy. <i>Nature Medicine</i> 2019;25(11):1715–1720. Shastri N, Nagarajan N, Lind KC, et al. Monitoring peptide processing for MHC class I molecules in the endoplasmic reticulum. <i>Curr Opin Immunol</i> 2014; <b>26</b>:123–127. Mpakali A, Maben Z, Stern LJ, et al. Molecular pathways for antigenic peptide generation by ER aminopeptidase 1. <i>Mol Immunol</i> 2018; <b>13</b>:50–57. James E, Bailey I, Sugiyarto G, et al. Induction of protective antitumor immunity through attenuation of ERAAP function. <i>J Immunol</i> 2013;190(11):5839–5846. Manguso RT, Pope HW, Zimmer MD, et al. In vivo CRISPR screening identifies Ptpn2 as a cancer immunoth","journal":"Regular and Young Investigator Award Abstracts","year":2020,"id":125575,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.946,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":572209,"name":"Lesley Young","orcid":"0000-0003-2118-1042","position":1,"is_corresponding":false},{"id":573016,"name":"Martin Quibell","orcid":null,"position":2,"is_corresponding":false},{"id":573017,"name":"Jason Shiers","orcid":null,"position":3,"is_corresponding":false},{"id":496496,"name":"Carmen Tong","orcid":null,"position":4,"is_corresponding":false},{"id":525247,"name":"Kristopher Clark","orcid":"0009-0007-1034-9483","position":5,"is_corresponding":false},{"id":573018,"name":"Edd James","orcid":null,"position":6,"is_corresponding":false},{"id":573019,"name":"Emma Reeves","orcid":null,"position":7,"is_corresponding":false},{"id":573020,"name":"Alihussein Remtulla","orcid":null,"position":8,"is_corresponding":false},{"id":573021,"name":"Henry Leonard","orcid":null,"position":9,"is_corresponding":false},{"id":572210,"name":"Camila de Almeida","orcid":"0000-0003-2652-2205","position":10,"is_corresponding":false},{"id":573022,"name":"Elisa Maria Lori","orcid":null,"position":11,"is_corresponding":false},{"id":489199,"name":"Nicola Ternette","orcid":"0000-0002-9283-0743","position":12,"is_corresponding":false},{"id":572211,"name":"Fergus E. Poynton","orcid":"0000-0002-3149-6198","position":13,"is_corresponding":false},{"id":572212,"name":"Andrew J. Leishman","orcid":"0000-0003-4273-8188","position":14,"is_corresponding":false},{"id":573015,"name":"Peter Joyce","orcid":null,"position":0,"is_corresponding":true}],"reference_count":8,"raw_metadata":null,"created_at":"2026-07-18T23:15:19.482428Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}