Abstract
Purpose
Despite the effectiveness of immunotherapy in advanced melanoma, the lack of clinically reliable biomarkers hinders precision medicine approaches. This study investigates the potential of immune time-resolved Förster resonance energy transfer (iFRET) as a novel tool for understanding immunotherapy response in melanoma.
Methods
Using tissue from a pilot phase II study of neoadjuvant talimogene laherparepvec (TVEC) before standard surgery, we explore iFRET's ability to assess PD-L1:PD-1 interactions in the tumor immune microenvironment (TiME) pre- and post-therapy.
Results
Responsive tumors demonstrated significant increases in iFRET efficiency, diverging from nonresponsive tumors that either decreased in checkpoint engagement or failed to demonstrate immune stimulation with therapy. Changes in PD-L1:PD-1 iFRET efficiency did not correlate with changes in PD-L1 expression. Instead, traditional biomarkers of PD-L1 expression and T-cell phenotyping did not reflect response trends and demonstrated significant heterogeneity inter- and intratumorally. Importantly, tumor-associated macrophage phenotype correlated significantly with TVEC response and the significantly high PD-L1:PD-1 interaction observed in the tumor beds of complete responders.
Conclusion
These findings underscore both the role of innate immune profiles in immunotherapy outcomes and the potential of iFRET to serve as a critical companion diagnostic in the classification of immune profiles. This research reveals crucial insights into factors affecting checkpoint function in tumors and emphasizes the need for further investigation into cell-specific interactions within the TiME. By expanding our understanding of distinct patient profiles for tailored therapeutic strategies, we underscore the importance of assessing this type of functional biomarker data in ongoing neoadjuvant trial designs to advance the goal of precision immunotherapy in patients with melanoma.
Despite the effectiveness of immunotherapy in advanced melanoma, the lack of clinically reliable biomarkers hinders precision medicine approaches. This study investigates the potential of immune time-resolved Förster resonance energy transfer (iFRET) as a novel tool for understanding immunotherapy response in melanoma.
Methods
Using tissue from a pilot phase II study of neoadjuvant talimogene laherparepvec (TVEC) before standard surgery, we explore iFRET's ability to assess PD-L1:PD-1 interactions in the tumor immune microenvironment (TiME) pre- and post-therapy.
Results
Responsive tumors demonstrated significant increases in iFRET efficiency, diverging from nonresponsive tumors that either decreased in checkpoint engagement or failed to demonstrate immune stimulation with therapy. Changes in PD-L1:PD-1 iFRET efficiency did not correlate with changes in PD-L1 expression. Instead, traditional biomarkers of PD-L1 expression and T-cell phenotyping did not reflect response trends and demonstrated significant heterogeneity inter- and intratumorally. Importantly, tumor-associated macrophage phenotype correlated significantly with TVEC response and the significantly high PD-L1:PD-1 interaction observed in the tumor beds of complete responders.
Conclusion
These findings underscore both the role of innate immune profiles in immunotherapy outcomes and the potential of iFRET to serve as a critical companion diagnostic in the classification of immune profiles. This research reveals crucial insights into factors affecting checkpoint function in tumors and emphasizes the need for further investigation into cell-specific interactions within the TiME. By expanding our understanding of distinct patient profiles for tailored therapeutic strategies, we underscore the importance of assessing this type of functional biomarker data in ongoing neoadjuvant trial designs to advance the goal of precision immunotherapy in patients with melanoma.
| Original language | English |
|---|---|
| Number of pages | 9 |
| Journal | JCO Oncology Advances |
| Volume | 2 |
| Early online date | 2 Jan 2025 |
| DOIs | |
| Publication status | Published - 2 Jan 2025 |