Article Impact Level: HIGH Data Quality: STRONG Summary of JCO Oncology Advances, 2, e2400049. https://doi.org/10.1200/OA-24-00049 Dr. Amanda R. Kirane et al.
Points
- The research explored immune time-resolved Förster resonance energy transfer (iFRET) as a novel method for evaluating immunotherapy response in melanoma, focusing on PD-L1:PD-1 interactions within the tumor immune microenvironment (TiME).
- Responsive tumors demonstrated increased iFRET efficiency, while nonresponsive tumors showed decreased checkpoint engagement or no immune stimulation, independent of PD-L1 expression levels or T-cell phenotyping.
- Tumor-associated macrophage phenotype was strongly correlated with therapy response, with complete responders exhibiting higher PD-L1:PD-1 interactions in tumor beds.
- iFRET emerged as a more reliable functional biomarker than traditional methods. It captures functional immune checkpoint interactions and addresses intratumoral and intertumoral heterogeneity.
- The study emphasizes incorporating iFRET-based biomarkers into neoadjuvant trial designs to improve precision immunotherapy strategies for melanoma patients.
Summary
This study investigates the potential of immune time-resolved Förster resonance energy transfer (iFRET) as a novel method for assessing immunotherapy response in melanoma. Despite the success of immunotherapy in advanced melanoma, the lack of reliable biomarkers has hindered precision medicine. The authors used tissue from a pilot phase II study of neoadjuvant talimogene laherparepvec (TVEC) followed by surgery to explore iFRET’s ability to assess PD-L1:PD-1 interactions in the tumor immune microenvironment (TiME) before and after therapy. The findings revealed that responsive tumors significantly increased iFRET efficiency, while nonresponsive tumors showed either decreased checkpoint engagement or no immune stimulation with therapy.
The study found that changes in PD-L1:PD-1 iFRET efficiency did not correlate with changes in PD-L1 expression, suggesting that traditional biomarkers like PD-L1 expression and T-cell phenotyping do not accurately reflect immunotherapy response. There was significant intratumoral and intertumoral heterogeneity observed in these biomarkers. Notably, the phenotype of tumor-associated macrophages was significantly correlated with TVEC response, with complete responders showing a significantly high PD-L1:PD-1 interaction in their tumor beds. These results highlight the complexity of tumor immune responses and suggest that iFRET could be a more reliable functional biomarker for assessing immunotherapy efficacy in melanoma.
The study underscores the importance of innate immune profiles in determining the effectiveness of immunotherapy. iFRET, by capturing functional interactions within the immune microenvironment, provides critical insights into checkpoint function and could serve as a companion diagnostic tool in precision immunotherapy. The findings suggest further research into cell-specific interactions in the TiME and emphasize the integration of iFRET-based functional biomarkers into neoadjuvant trial designs to optimize therapeutic strategies for melanoma patients.
Link to the article: https://ascopubs.org/doi/10.1200/OA-24-00049
References Kirane, A. R., Lee, D., Lowe, M., Ahmad, M. U., Sharma, S., Serasanambati, M., Applebee, C. J., Safrygina, E., Betof Warner, A., Wang, J., Le, S., Larijani, B., & Maverakis, E. (2025). 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, 2, e2400049. https://doi.org/10.1200/OA-24-00049
