Circulating IFNγ-associated protein signatures predict response to neoadjuvant immunotherapy in patients with stage III melanoma
Cancer Cell International, 2025
Yang F., Lim S., da Silva I., Yu L., Conway J., Menzies A., Long G., Yang J., Rizos H.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Oncology Immunotherapy | Patient Stratification | Serum |  Olink Explore 3072/384 |
Abstract
Background
Immune checkpoint inhibitors (ICIs), such as anti-programmed cell death protein 1 (PD-1) and anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4), have transformed the management of stage III melanoma in the neoadjuvant setting. However, a substantial proportion of patients do not derive benefit from ICI therapy. To improve clinical outcomes, there remains a critical unmet need to identify early biomarkers of response to neoadjuvant immunotherapy in stage III melanoma.
Methods
In this study, we performed longitudinal serum proteomic profiling in 39 patients undergoing neoadjuvant combination anti-PD-1 and anti-CTLA-4 therapy. Using a multiplex proximity extension assay, we measured 702 proteins at three timepoints: baseline, early on-treatment (3–4 weeks after treatment initiation), and pre-surgery (4–8 weeks post-treatment).
Results
The most pronounced differences between major pathological responders (MPR) and non-MPR patients were detected at baseline and were linked to interferon gamma (IFNγ) signalling, but these differences diminish at later timepoints. A 10-protein IFNγ-associated signature derived from baseline serum profile achieved an AUC of 0.68 for predicting pathological response, comparable to a previously reported tumour-based IFNγ gene signature (AUC = 0.67).
Conclusions
These findings support the use of circulating protein signatures as minimally invasive, scalable biomarkers to inform early treatment decisions in the neoadjuvant setting.