The antigen processing machinery of a cell shapes the repertoire of peptides presented for immunosurveillance 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 transformed cancer cells. During direct presentation, endoplasmic reticulum aminopeptidases (ERAPs) can further process peptides translocated into the ER following intracellular proteasomal degradation, thereby editing the final pool of ligands able to compete for binding to HLA-I molecules. Hence, modulation of ERAP processing presents an opportunity to profoundly alter the immune landscape of cancer. Here, we developed a highly potent and selective allosteric inhibitor of ERAP1, and showed that pharmacological inhibition of multiple ERAP1 haplotypes across several cancers is able to unmask an alternative suite of tumour-associated peptides that are presented by a diverse array of HLA-I molecules.

Crucially, several epitopes either significantly upregulated or uniquely presented following ERAP1 inhibition were recognised by pre-existing CD8+ T cell populations in multiple healthy human donors, demonstrating that pharmacological inhibition of ERAP1 may be able to both augment anti-tumour immunity and subvert tumour immune evasion mechanisms by unveiling an alternative subset of epitopes with the capacity to prime novel cytotoxic T cell responses, leading to our lead candidate molecule entering clinical trials in early 2023.