Serum Levels of Soluble Urokinase Plasminogen Activator Receptor Predict Tumor Response and Outcome to Immune Checkpoint Inhibitor Therapy

Sven H Loosen; Joao Gorgulho; Markus S Jördens; Maximilian Schulze-Hagen; Fabian Beier; Mihael Vucur; Anne T Schneider; Christiane Koppe; Alexander Mertens; Jakob N Kather; Frank Tacke; Verena Keitel; Tim H Brümmendorf; Christoph Roderburg; Tom Luedde

doi:10.3389/fonc.2021.646883

Serum Levels of Soluble Urokinase Plasminogen Activator Receptor Predict Tumor Response and Outcome to Immune Checkpoint Inhibitor Therapy

Front Oncol. 2021 Apr 1:11:646883. doi: 10.3389/fonc.2021.646883. eCollection 2021.

Authors

Sven H Loosen^{1

2}, Joao Gorgulho^{3

4}, Markus S Jördens¹, Maximilian Schulze-Hagen⁵, Fabian Beier⁶, Mihael Vucur¹, Anne T Schneider³, Christiane Koppe³, Alexander Mertens¹, Jakob N Kather², Frank Tacke⁷, Verena Keitel¹, Tim H Brümmendorf⁶, Christoph Roderburg^{1

7}, Tom Luedde¹

Affiliations

¹ Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
² Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
³ Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, University Hospital RWTH Aachen, Aachen, Germany.
⁴ Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
⁵ Department of Diagnostic and Interventional Radiology, University Hospital RWTH Aachen, Aachen, Germany.
⁶ Department of Medicine IV, University Hospital RWTH Aachen, Aachen, Germany.
⁷ Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany.

Abstract

Background: Immune checkpoint inhibitors (ICIs) have led to a paradigm shift in cancer therapy, improving outcomes in the treatment of various malignancies. However, not all patients benefit to the same extend from ICI. Reliable tools to predict treatment response and outcome are missing. Soluble urokinase plasminogen activator receptor (suPAR) is a marker of immune activation, whose levels are prognostic in various cancers. We evaluated circulating suPAR levels as a novel predictive and prognostic biomarker in patients receiving ICI therapy for solid tumors.

Methods: A total of n = 87 patients receiving ICI therapy for different solid malignancies as well as 32 healthy controls were included into this study. Serum levels of suPAR were measured by ELISA prior to and sequentially at two time points during ICI therapy.

Results: Baseline suPAR serum levels were significantly higher in solid tumor patients compared to healthy controls. Importantly, patients with low suPAR levels both before or during ICI treatment were more likely to have a favorable response to treatment at three and six months, respectively. This finding was confirmed by multivariate binary logistic regression analysis including several clinicopathological parameters. Moreover, circulating suPAR levels before and during therapy were an independent prognostic factor for overall survival (OS). As such, patients with initial suPAR levels above our ideal prognostic cut-off value (4.86 ng/ml) had a median OS of only 160 days compared to 705 days for patients with suPAR levels below this cut-off value. Finally, low baseline suPAR levels identified a subgroup of patients who experienced ICI-related side effects which in turn were associated with favorable treatment response and outcome.

Conclusion: Our data suggest that measurements of suPAR serum levels are a previously unknown, easily accessible tool to predict individual treatment response and outcome to ICI therapy. Circulating suPAR might therefore be implemented into stratification algorithms to identify the ideal candidates for ICI treatment.

Keywords: IRAE; biomarker; checkpoint inhibitors; immunotherapy; nivolumab; pembrolizumab; prognosis.