Cancer cells and viruses often slip past the immune system by sabotaging the molecular machinery that puts peptide fragments on the cell surface for T cells to detect. This project tackles a specific blind spot in that machinery: how two proteins—tapasin and ERAP1—work together to either save or destroy those peptide fragments. The problem is that current computer models can predict which peptides will be presented on healthy cells, but they fail when cells are under attack and the presentation pathway is corrupted. The researchers have observed that when tapasin is missing—common in many cancers and viral infections—ERAP1 over-trims peptides, destroying them before they can reach the cell surface. This makes the target cell invisible to the immune system. If this project succeeds, it could identify which patients’ tumours would respond to drugs that inhibit ERAP1, restoring the peptide display and making cancers vulnerable to existing immunotherapies like checkpoint inhibitors. It could also guide the design of vaccines that work even when cells try to hide. This is fundamental science with a clear translational path: understanding a precise molecular interaction to predict who will benefit from a treatment and why.
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Antigen presentation on target cells is essential to induce an effective immune response. Understanding how peptides are generated and subsequently presented at the cell surface has been essential in developing immunotherapy treatments and vaccines. These treatments usually focus on high affinity cancer or viral peptides which bind strongly to major histocompatibility complex class I (MHC-I; called HLA-I in humans) molecules. In recent years in silico methods predicting which peptides are presented by HLA molecules have become increasingly reliable. However, they lack precision in pathological conditions, such as when cancer or virally infected cells evade the immune response by interfering with peptide generation and presentation, rendering target cells invisible to the immune system, highlighting a knowledge gap. Our project aims to deepen our understanding of the HLA-I peptide presentation pathway and how it is altered during immune evasion, enabling the development of new therapeutic strategies and/or biomarkers to stratify patients that could benefit from these therapies. The processing and presentation of peptide antigens involves tapasin and endoplasmic reticulum aminopeptidase 1, ERAP1, which edit peptides for presentation by HLA-I molecules. Tapasin assists peptide binding to HLA, but the level of assistance depends on the specific HLA; characterised as being tapasin-dependent or -independent. Tapasin expression is often reduced in cancers and some viral infections, which leads to unstable peptide-HLA complexes, as the peptides are poorer binders, resulting in low levels of cell surface presentation. ERAP1 trims peptide precursors to their final length for HLA loading but can also destroy peptides by overtrimming, preventing their binding to HLA and subsequent cell surface presentation to CD8+ T-cells. Abrogating ERAP1 activity can prevent this overtrimming leading to presentation and activation of CD8+ T-cells. Whilst the function of tapasin and ERAP1 have been studied extensively, understanding how these molecules may work together is limited. We observed the loss of T cell epitopes when tapasin was absent. However, their presentation was restored when ERAP1 activity was inhibited, suggesting they were overtrimmed. This level of ERAP1 overtrimming is greater when tapasin is absent, indicating a synergistic effect of tapasin and ERAP1 on peptide presentation where tapasin can perform a protective role from ERAP1 overtrimming. Importantly, this protection may also be dependent on the level of interaction between peptide-MHC and tapasin. Therefore, we hypothesise that the ability of ERAP1 to destroy peptides is determined by the absence of tapasin and the tapasin-dependence of the HLA molecule expressed. The project aims are (1) to investigate the combined role of tapasin and ERAP1 by measuring the effect of tapasin and ERAP1 loss on peptides presented on a panel of different HLA alleles; this will identify HLA alleles for which ERAP1 inhibition has the greatest effect on the peptides presented and (2) to assess whether presentation of ERAP1-sensitive peptides, lost after tapasin downregulation, can be restored by ERAP1 inhibitor treatment. This knowledge is vital in enabling us to predict which HLA molecules are most affected by ERAP1 and whether altering ERAP1 activity could restore tumour antigenic epitopes in patients expressing tapasin-dependent/independent HLA alleles in tapasin downregulated tumours, sensitising tumours to immunotherapies (e.g. checkpoint blockade inhibition). Ultimately, understanding the combined role of tapasin and ERAP1 in peptide presentation will enable the design and translation of immunotherapy treatments, such as vaccines that resist immune evasion, and aid in identifying patients most likely to benefit.
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