New research highlights the potential of a novel diagnostic tool to determine the innate immune profiles of patients with stage 2 melanoma and help predict who is most likely to respond to immunotherapy treatment.
Using immune time-resolved Förster resonance energy transfer (iFRET), researchers measured functional biomarkers and provided real-time information to profile immune responses in melanoma patients. For patients with stage 2 melanoma, iFRET was able to predict the value and effectiveness of neoadjuvant oncolytic virus therapy.
The UK and US researchers used tissue from a pilot phase II study of neoadjuvant talimogene laherparepvec (TVEC) – this is a modified oncolytic virus injected directly into melanoma to stimulate an immune response and destroy cancer cells before standard surgery.
They used iFRET to determine how the therapy affected immune checkpoint activity, specifically examining the interactions of the proteins programmed death-ligand 1 (PD-L1) on tumour cells or immune cells and programmed cell death protein 1 (PD-1) on immune cells in the tumour immune microenvironment before and after therapy.
The tumours responsive to immunotherapy showed a significant increase in iFRET efficiency, reflecting a more active immune response and the likelihood of a better response. Unresponsive tumours either showed decreased checkpoint engagement with fewer PD-L1:PD-1 interactions or failed to demonstrate an immune response to therapy.
The researchers also found that traditional biomarkers did not reliably predict a tumour’s response to immunotherapy, as the level of checkpoint engagement did not link to changes in PD-L1 expression.
However, macrophage behaviour did correlate with patients who responded to the treatment and those who did not, suggesting that tumour-associated macrophage phenotypes play a key role in the effectiveness of TVEC therapy.
Clinicians could potentially reprogramme the tumour’s immune environment by targeting macrophages in non-responding patients, the researchers concluded.
In addition, strong PD-L1:PD-1 interactions in the tumour beds correlated with a better response to the treatment.
The findings highlight the importance of examining the whole immune response environment to predict which patients would be better served by either surgery or immune checkpoint blockade via immunotherapy.
In future work, the team will attempt to characterise all cells contributing to the immune checkpoint interaction, further improving patient stratification and personalised medicine.
Reference
Kirane, A et al. Toward Functional Biomarkers of Response to Neoadjuvant Oncolytic Virus in Stage II Melanoma: Immune-Förster Resonance Energy Transfer and the Dynamic Tumor Immune Microenvironment. JCO Oncology Advances 2025; Jan 02: DOI: 10.1200/OA-24-00049.
