Related Experiment Video
Updated: Jun 8, 2025
In Vivo Immunogenicity Screening of Tumor-Derived Extracellular Vesicles by Flow Cytometry of Splenic T Cells
Published on: September 23, 2021
Soluble and EV-bound CD27 act as antagonistic biomarkers in patients with solid tumors undergoing immunotherapy
Joao Gorgulho1,2, Sven H Loosen3,4, Ramsha Masood5
1Department of Oncology, Hematology and Bone Marrow Transplantation With Section of Pneumology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
Background:
The major breakthrough in cancer therapy with immune checkpoint inhibitors (ICIs) has highlighted the important role of immune checkpoints in antitumoral immunity. However, most patients do not achieve durable responses, making biomarker research in this setting essential. CD27 is a well known costimulatory molecule, however the impact of its soluble form in ICI is poorly investigated. Therefore, we aimed at testing circulating concentrations of soluble CD27 (sCD27) and CD27 bound to extracellular vesicles (EVs) as potential biomarkers to predict response and overall survival (OS) in patients undergoing ICI.
Methods:
Serum and plasma levels of sCD27 were assessed by immunoassay in three patient cohorts (n = 187) with advanced solid malignancies including longitudinal samples (n = 126): a training (n = 84, 210 specimens, Aachen ICI) and validation cohort (n = 70, 70 specimens, Hamburg ICI), both treated with ICI therapy, and a second independent validation cohort (n = 33, 33 specimens, Hamburg non-ICI) undergoing systemic therapy without any ICI. In a subset (n = 36, 36 baseline and 108 longitudinal specimens), EV-bound CD27 from serum was measured, while EV characterization studies were conducted on a fourth cohort (n = 45).
Results:
In the Aachen and Hamburg ICI cohorts, patients with lower circulating sCD27 levels before and during ICI therapy had a significantly longer progression-free survival (PFS) and OS compared to patients with higher levels, a finding that was confirmed by multivariate analysis (MVA) (Aachen ICI: pPFS = 0.012, pOS = 0.001; Hamburg ICI: pPFS = 0.040, pOS = 0.004) and after randomly splitting both cohorts into training and validation. This phenomenon was not observed in the Hamburg non-ICI cohort, providing a rationale for the predictive biomarker role of sCD27 in immune checkpoint blockade. Remarkably, EV-bound CD27 baseline levels and dynamics during ICI therapy also emerged as potent predictive biomarkers, acting however antagonistically to soluble sCD27, i.e. higher levels were associated with PFS and OS benefit. Combining both molecules ("multi-CD27" score) enhanced the predictive ability (HRPFS: 17.21 with p < 0.001, HROS: 6.47 with p = 0.011).
Conclusion:
Soluble and EV-bound CD27 appear to have opposing immunomodulatory functions and may represent easily measurable, non-invasive prognostic markers to predict response and survival in patients undergoing ICI therapy.
Insights
Soluble CD27 (sCD27) and extracellular vesicle-bound CD27 (EV-CD27) show opposing roles in predicting patient response to immune checkpoint inhibitors (ICIs). Lower sCD27 and higher EV-CD27 levels correlate with better survival, offering new prognostic biomarkers for ICI therapy.
Area of Science:
- Immunology and Cancer Therapy
- Biomarker Discovery
- Molecular Diagnostics
Background:
- Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, but response rates vary significantly.
- Identifying predictive biomarkers is crucial for optimizing ICI therapy and patient outcomes.
- The role of soluble CD27 (sCD27) and extracellular vesicle-bound CD27 (EV-CD27) in ICI response remains underexplored.
Purpose of the Study:
- To investigate circulating concentrations of sCD27 and EV-bound CD27 as potential biomarkers for predicting response to ICI therapy.
- To assess the prognostic value of sCD27 and EV-CD27 for progression-free survival (PFS) and overall survival (OS) in patients with advanced solid malignancies.
- To evaluate the combined predictive ability of sCD27 and EV-CD27 using a novel 'multi-CD27' score.
Main Methods:
- Serum and plasma sCD27 levels were measured using immunoassay in three patient cohorts (n=187) undergoing ICI or non-ICI systemic therapy.
- EV-bound CD27 was quantified in serum from a subset of patients (n=36), with EV characterization performed on a separate cohort (n=45).
- Longitudinal samples were analyzed to track biomarker dynamics during ICI treatment.
Main Results:
- Lower baseline and during-treatment sCD27 levels were significantly associated with longer PFS and OS in ICI-treated patients (p<0.05).
- Conversely, higher EV-bound CD27 levels (baseline and dynamic) predicted improved PFS and OS, demonstrating an antagonistic role to sCD27.
- A combined 'multi-CD27' score significantly enhanced predictive accuracy for PFS (HR=17.21, p<0.001) and OS (HR=6.47, p=0.011).
Conclusions:
- Soluble and EV-bound CD27 exhibit opposing immunomodulatory functions in the context of ICI therapy.
- sCD27 and EV-bound CD27 are promising, easily measurable, non-invasive prognostic biomarkers for predicting ICI response and patient survival.
- The 'multi-CD27' score offers a refined tool for patient stratification and treatment selection in ICI therapy.
