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

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

doi:10.3389/fonc.2021.646883

Abstract

BackgroundImmune 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.MethodsA 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.ResultsBaseline 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.ConclusionOur 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.

Highlights

Immune checkpoint inhibitors (ICIs) have led to a paradigm shift in cancer therapy, improving outcomes in the treatment of various malignancies
A total of n = 87 patients with advanced tumor stage scheduled to receive immune checkpoint inhibitor (ICI) therapy were included into this study prior to the first ICI administration
There was no significant difference in baseline Soluble urokinase plasminogen activator receptor (suPAR) levels regarding the scheduled ICI regimen (Figure 1D) as well as between patients who did or did not receive systemic cancer therapy previously (Figure 1E)

Summary

Introduction

Immune checkpoint inhibitors (ICIs) have led to a paradigm shift in cancer therapy, improving outcomes in the treatment of various malignancies. We evaluated circulating suPAR levels as a novel predictive and prognostic biomarker in patients receiving ICI therapy for solid tumors. While ICIs can achieve higher response and survival rates compared to conventional chemotherapy in several tumor entities, a subset of patients does not respond to immunotherapy. Mostly tissue based, markers such as the expression of PD-L1, the tumor mutational burden (TMB) or the microsatellite instability (MSI) status have been suggested to predict ICI treatment response in selected tumor entities [3, 6,7,8], the identification of the ideal ICI patients who benefit from ICI has remained challenging

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Conclusion