Soluble and EV-bound CD27 act as antagonistic biomarkers in patients with solid tumors undergoing immunotherapy

BackgroundThe major breakthrough in cancer therapy with immune checkpoint inhibitors (ICIs) has highlighted the important role of these molecules in antitumoral immunity. However, most patients do not achieve durable responses, making biomarker research in this setting essential. 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.MethodsSerum and plasma levels of sCD27 were assessed by multiplex 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).ResultsIn 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 (Aachen ICI: pPFS=0.012, pOS=0.001; Hamburg ICI: pPFS=0.040, pOS=0.004). This finding could not be replicated 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 and dynamics during ICI therapy also emerged as a potent predictive biomarker, acting however antagonistically to soluble sCD27, whereas in this case patients with higher levels showed a clear PFS and OS benefit. A combined “multi-CD27� score including both molecules showed the best predictive ability (HRPFS: 17.21 with p<0.001, HROS: 6.47 with p=0.011).ConclusionsSoluble 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 under ICI therapy.Legal entity responsible for the studyThe authors.FundingERC, BMBF, DFG, DKH, Ernst-Jung Foundation, UCCH.DisclosureJ. Von Felden: Financial Interests, Institutional, Other, Honoraries: Roche, AstraZeneca. All other authors have declared no conflicts of interest.