Inhibiting the ERAP1 enzyme in melanoma cells changed approximately half of the peptides displayed on their surface, actually improving immune recognition potential by presenting more high-quality peptide targets.
~50% of displayed peptides changedERAP1 inhibition altered approximately half of the 3,204 peptides displayed on melanoma cell surfaces, with improved average binding quality — making tumors potentially more immunogenic.
What the researchers found
Treatment of A375 melanoma cells with an ERAP1 inhibitor altered the presentation of approximately half of the 3,204 identified peptides displayed on MHC class I molecules, including about one third of peptides predicted to bind tightly to MHC-I. The inhibitor did not reduce cell-surface MHC-I expression levels.
The most surprising finding was that ERAP1 inhibition actually improved the average predicted MHC-I binding affinity of displayed peptides. This occurred because the enzyme's normal activity was destroying many high-quality potential epitopes (9–12 amino acid peptides) while allowing suboptimal long peptides to persist. Blocking ERAP1 reduced presentation of these suboptimal long peptides and increased presentation of many high-affinity shorter peptides — essentially improving the immunogenicity of the tumor cells.
Why it matters
Immune checkpoint inhibitors (like pembrolizumab and nivolumab) have revolutionized cancer treatment, but many patients don't respond because their tumors don't present enough recognizable peptide targets. This study introduces a fundamentally different approach: rather than boosting the immune response, manipulate what the cancer cells display on their surface to make them more immunogenic. If ERAP1 inhibitors can be developed into drugs, they could complement existing immunotherapies by making unresponsive tumors visible to the immune system.
How the study worked
Researchers treated A375 melanoma cells with a potent ERAP1 inhibitor and analyzed the presented MHC class I peptide repertoire. MHC-I molecules were isolated from treated and untreated cells, bound peptides were eluted, and identified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Peptide length distributions, binding motifs, and predicted MHC-I binding affinities were compared between treated and control conditions.
What this study cannot tell us
This study was conducted entirely in cell culture using a single melanoma cell line (A375). Whether ERAP1 inhibition would enhance anti-tumor immune responses in living organisms was not tested. The peptide changes observed in vitro may differ from those occurring in the complex tumor microenvironment. The ERAP1 inhibitor's selectivity, pharmacokinetics, and potential off-target effects on normal cells (which also use ERAP1 for peptide processing) were not addressed. Whether the altered peptides would actually be recognized by patient T cells remains unknown.
How to read the evidence
This is an in vitro cell line study providing mechanistic proof-of-concept. While the mass spectrometry analysis is rigorous and the findings are novel, no animal or human immunological data supports the therapeutic hypothesis. The evidence is at the early preclinical stage.
When this study was published
Published in 2019, this study is about 6 years old. Since then, interest in manipulating antigen processing for immunotherapy has grown, and ERAP1 has become an increasingly recognized target. The findings remain scientifically relevant and have not been superseded.
The bigger picture
The immunopeptidome — the collection of peptides displayed on cell surfaces for immune surveillance — is a rapidly growing area of cancer research. This study demonstrates that the peptide processing machinery can be pharmacologically manipulated to enhance tumor immunogenicity. This concept of 'editing' the immunopeptidome represents an emerging therapeutic strategy that could synergize with checkpoint inhibitors, cancer vaccines, and adoptive T-cell therapies by ensuring cancer cells display better targets for immune attack.
Questions still open
- Would ERAP1 inhibition in animal models lead to enhanced anti-tumor immune responses and tumor rejection?
- Could ERAP1 inhibitors be combined with checkpoint inhibitors to convert immunotherapy non-responders into responders?
- What would be the effects of systemic ERAP1 inhibition on normal cell antigen presentation and immune homeostasis?
Common questions
How does ERAP1 affect cancer immunotherapy?
Could this approach work alongside existing cancer immunotherapies?
Read the original research
Editing the immunopeptidome of melanoma cells using a potent inhibitor of endoplasmic reticulum aminopeptidase 1 (ERAP1).
Cancer immunology, immunotherapy : CII, 68(8), 1245-1261
Citation
Koumantou, Despoina; Barnea, Eilon; Martin-Esteban, Adrian; Maben, Zachary; Papakyriakou, Athanasios; Mpakali, Anastasia; Kokkala, Paraskevi; Pratsinis, Harris; Georgiadis, Dimitris; Stern, Lawrence J; Admon, Arie; Stratikos, Efstratios. (2019). Editing the immunopeptidome of melanoma cells using a potent inhibitor of endoplasmic reticulum aminopeptidase 1 (ERAP1).. Cancer immunology, immunotherapy : CII, 68(8), 1245-1261. https://doi.org/10.1007/s00262-019-02358-0