Abstract 4153: First-in-class inhibitors of ERAP1 alter the HLA-I-restricted cancer immunopeptidome leading to the generation of novel peptides presented for immune recognition

Abstract The antigen processing machinery of a cell shapes the repertoire of peptides presented for immune recognition on the cell surface. Human leukocyte antigen class I (HLA-I) molecules present peptides that are recognised by both CD8+ T cells and NK cells, and these complexes play a vital role in the recognition and eradication of malignant cells. During direct presentation, the endoplasmic reticulum aminopeptidase 1 (ERAP1) enzyme processes a subset of HLA-I ligand precursors which are translocated into the endoplasmic reticulum (ER) following intracellular proteasomal degradation. Here, we show that inhibition of ERAP1 with highly potent and selective small molecule inhibitors drives significant qualitative and quantitative changes in the HLA-I-restricted immunopeptidome, resulting in the generation of altered and novel peptides from tumour-associated antigens that are then presented on HLA-I molecules. A major consequence of inhibiting the processing of precursor ligands by ERAP1 within the ER of cancer cells was not only the generation of unique peptides which were not detectable under baseline conditions, but a shift in the peptide length distribution towards longer HLA-I-restricted peptides. Importantly, we demonstrate that the degree of bias towards longer HLA-I-bound ligands uniquely presented following ERAP1 inhibition was governed by both ERAP1 and HLA-I haplotypes. Such dramatic changes in the peptide repertoire presented for immune recognition have the potential to enhance anti-tumoural immunogenicity through T cell recognition of a novel cancer immunopeptidome, and, in addition to global shifts in the peptide length distributions, unique peptides presented for immune recognition during ERAP1 inhibition may be used as biomarkers for monitoring activity of this novel therapeutic approach in the clinic. Citation Format: Wayne Paes, Andrew Leishman, Kate Anderton, Hanqing Liao, Isaac Woodhouse, Robert Parker, Annalisa Nicastri, Peter Joyce, Nicola Ternette. First-in-class inhibitors of ERAP1 alter the HLA-I-restricted cancer immunopeptidome leading to the generation of novel peptides presented for immune recognition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4153.