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

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.

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High baseline soluble urokinase plasminogen activator receptor (suPAR) serum levels indicate adverse outcome after resection of pancreatic adenocarcinoma

Carcinogenesis ◽

10.1093/carcin/bgz033 ◽

2019 ◽

Vol 40 (8) ◽

pp. 947-955 ◽

Cited By ~ 4

Author(s):

Sven H Loosen ◽

Frank Tacke ◽

Niklas Püthe ◽

Marcel Binneboesel ◽

Georg Wiltberger ◽

...

Keyword(s):

Plasminogen Activator ◽

Pancreatic Adenocarcinoma ◽

Tumor Resection ◽

Serum Levels ◽

Urokinase Plasminogen Activator ◽

Healthy Controls ◽

Urokinase Plasminogen Activator Receptor ◽

High Baseline ◽

Plasminogen Activator Receptor

Abstract Surgical resection represents the only potentially curative therapy for patients with pancreatic adenocarcinoma (PDAC), an aggressive malignancy with a very limited 5-year survival rate. However, even after complete tumor resection, many patients are still facing an unfavorable prognosis underlining the need for better preoperative stratification algorithms. Here, we explored the role of the secreted glycoprotein soluble urokinase plasminogen activator receptor (suPAR) as a novel circulating biomarker for patients undergoing resection of PDAC. Serum levels of suPAR were measured by enzyme-linked immunosorbent assay (ELISA) in an exploratory as well as a validation cohort comprising a total of 127 PDAC patients and 75 healthy controls. Correlating with a cytoplasmic immunohistochemical expression of uPAR in PDAC tumor cells, serum levels of suPAR were significantly elevated in PDAC patients compared to healthy controls and patient with PDAC precursor lesions. Importantly, patients with high preoperative suPAR levels above a calculated cutoff value of 5.956 ng/ml showed a significantly reduced overall survival after tumor resection. The prognostic role of suPAR was further corroborated by uni- and multivariate Cox-regression analyses including parameters of systemic inflammation, liver and kidney function as well as clinico-pathological patients’ characteristics. Moreover, high baseline suPAR levels identified those patients particularly susceptible to acute kidney injury and surgical complications after surgery. In conclusion, our data suggest that circulating suPAR represents a novel prognostic marker in PDAC patients undergoing tumor resection that might be a useful addition to existing preoperative stratification algorithms for identifying patients that particularly benefit from extended tumor resection.

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Serum levels of soluble urokinase plasminogen activator receptor is associated with parasitemia in children with acute Plasmodium falciparum malaria infection

Parasite Immunology ◽

10.1111/j.0141-9838.2004.00695.x ◽

2004 ◽

Vol 26 (5) ◽

pp. 207-211 ◽

Cited By ~ 32

Author(s):

M. Perch ◽

PE. Kofoed ◽

T. K. Fischer ◽

F. Co ◽

L. Rombo ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Plasminogen Activator ◽

Falciparum Malaria ◽

Malaria Infection ◽

Plasmodium Falciparum Malaria ◽

Serum Levels ◽

Urokinase Plasminogen Activator ◽

Urokinase Plasminogen Activator Receptor ◽

Plasminogen Activator Receptor

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Soluble urokinase plasminogen activator receptor (suPAR) as a novel biomarker in patients undergoing resection of pancreatic adenocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.248 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 248-248

Author(s):

Sven H Loosen ◽

Marcel Binnebösel ◽

Thomas Longerich ◽

Christoph Roderburg ◽

Christian Trautwein ◽

...

Keyword(s):

Plasminogen Activator ◽

Pancreatic Adenocarcinoma ◽

Tumor Resection ◽

Serum Levels ◽

Healthy Controls ◽

Urokinase Plasminogen Activator Receptor ◽

Tissue Samples ◽

Pdac Tissue ◽

Plasminogen Activator Receptor

248 Background: Surgical resection represents the only potentially curative therapy for patients with pancreatic adenocarcinoma (PDAC), an aggressive malignancy with a very limited 5-year survival rate. However, even after successful R0 tumor resection, some patients are still facing an unfavourable prognosis underlining the need for better preoperative stratification algorithms. The soluble urokinase plasminogen activator receptor (suPAR) was recently described as a promising new biomarker for different clinical conditions including cancer. Here, we evaluated the potential role of circulating suPAR as a biomarker in patients undergoing resection of PDAC. Methods: Expression levels of uPAR, the membrane-bound source of circulating suPAR, were analysed in PDAC tissue samples using IHC. Serum levels of suPAR were measured by ELISA in an exploratory as well as a validation cohort comprising a total of 127 PDAC patients and 75 healthy controls. Results were correlated with clinical data. Results: Correlating with a high immunohistochemical expression of uPAR in PDAC tissue samples, serum levels of suPAR were significantly elevated in PDAC patients compared to healthy controls. Importantly, patients with high preoperative suPAR levels above a calculated cut-off value of 5.956 ng/ml showed a significantly reduced overall survival after tumor resection. The prognostic role of suPAR was further corroborated by uni- and multivariate Cox-regression analyses including parameters of systemic inflammation, liver and kidney function as well as clinico-pathological patients’ characteristics. Moreover, high baseline suPAR levels identified those patients particularly susceptible to acute kidney injury after surgery. Conclusions: Our data suggest that circulating suPAR represents a novel prognostic marker in PDAC patients undergoing tumor resection that might be a useful addition to existing preoperative stratification algorithms for identifying patients that particularly benefit from extended tumor resection.

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Serum levels of soluble urokinase plasminogen activator receptor (suPAR) as a marker of tuberculosis treatment efficacy

Indian Journal of Tuberculosis ◽

10.1016/j.ijtb.2017.01.012 ◽

2017 ◽

Vol 64 (3) ◽

pp. 206-211 ◽

Cited By ~ 3

Author(s):

V. Indumati ◽

V. Vijay ◽

D. Krishnaswamy ◽

V. Rajeshwari ◽

A. Ramesh ◽

...

Keyword(s):

Plasminogen Activator ◽

Treatment Efficacy ◽

Serum Levels ◽

Urokinase Plasminogen Activator ◽

Tuberculosis Treatment ◽

Urokinase Plasminogen Activator Receptor ◽

Plasminogen Activator Receptor

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Plasma levels of intact and cleaved urokinase plasminogen activator receptor (uPAR) in men with clinically localised prostate cancer

Journal of Clinical Pathology ◽

10.1136/jclinpath-2017-204475 ◽

2017 ◽

Vol 70 (12) ◽

pp. 1063-1068

Author(s):

Gitte Kristensen ◽

Kasper Drimer Berg ◽

Solvej Lippert ◽

Ib Jarle Christensen ◽

Klaus Brasso ◽

...

Keyword(s):

Prostate Cancer ◽

Plasminogen Activator ◽

Plasma Levels ◽

Specific Antigen ◽

Roc Curves ◽

Urokinase Plasminogen Activator ◽

Clinicopathological Parameters ◽

Prognostic Information ◽

Urokinase Plasminogen Activator Receptor ◽

Plasminogen Activator Receptor

AimsLymph node metastasis (N1) is an adverse prognostic factor for men with clinically localised prostate cancer (PCa), but the prediction of N1 disease remains difficult. Urokinase plasminogen activator receptor (uPAR) plays an important role in angiogenesis and tumorigenesis. We analysed whether plasma levels of the soluble uPAR forms uPAR(I-III), uPAR(II-III) and uPAR(I) were associated with the risk of N1 disease in men with clinically localised PCa.MethodsThe present study includes all men (n=518) who underwent radical prostatectomy (RP) for clinically localised PCa, 29 of whom had N1 disease. Soluble uPAR forms were measured using three time-resolved fluorescence immunoassays. The prognostic value of the different uPAR forms together with clinicopathological parameters for N1 disease were analysed using logistic regression, receiver operating characteristic (ROC) regression analysis and quantified using the areas under the ROC curve (AUC).ResultsAll soluble uPAR levels were significantly (p=0.03) higher in patients with N1 disease compared with patients with N0/x disease. ROC curves including clinical tumour stage, biopsy Gleason score, prostate-specific antigen and percent positive biopsies had an AUC of 87.7% for prediction of N1 disease. With the addition of uPAR(I) to the model, the AUC increased to 88.4%.ConclusionsAddition of uPAR(I) level to known diagnostic parameters did not increase the prediction of N1 disease following RP in men with clinically localised PCa. Our results indicate that the plasma levels at diagnosis of the different uPAR forms do not hold important predictive or prognostic information in men with clinically localised PCa.

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Soluble urokinase plasminogen activator receptor (suPAR) as a novel serum biomarker for patients undergoing resection of colorectal liver metastases.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.309 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 309-309

Author(s):

Sven H Loosen ◽

Marcel Binneboesel ◽

Christian Klink ◽

Tom Florian Ulmer ◽

Thomas Longerich ◽

...

Keyword(s):

Acute Kidney Injury ◽

Liver Metastases ◽

Plasminogen Activator ◽

Surgical Resection ◽

Colorectal Liver Metastases ◽

Kidney Injury ◽

Serum Levels ◽

Healthy Controls ◽

Urokinase Plasminogen Activator Receptor ◽

Plasminogen Activator Receptor

309 Background: In colorectal cancer (CRC), the liver is the most common site of metastasis. Surgical resection represents the standard potentially curative therapy for patients with colorectal liver metastases (CRLM). However, 5-year survival rates after resection do not exceed 50%, and despite existing preoperative stratification algorithms it is still not fully understood which patients benefit most from surgery. The soluble urokinase plasminogen activator receptor (suPAR) has recently evolved as a promising biomarker for distinct clinical conditions. Here, we examined a potential role of circulating suPAR as a biomarker in patients undergoing resection of CRLM. Methods: Expression levels of uPAR, the membrane-bound source of circulating suPAR, were analysed in tissue samples of CRLM using RT-PCR and IHC. SuPAR serum levels were measured by ELISA in 104 patients undergoing surgical resection of CRLM as well as 50 healthy controls. Results were correlated with clinical data. Results: In line with an upregulation of uPAR in the CRLM tissue, serum levels of suPAR were significantly elevated in patients with CRLM compared to healthy controls. Patients with preoperative suPAR serum levels above our defined ideal cut-off value of 4.83 ng/ml showed a strikingly reduced overall survival after resection of CRLM, which could be confirmed for right- and left-sided primary CRC. Importantly, none of these patients reached long-term survival compared to patients with preoperative suPAR serum concentrations below the cut-off value. Moreover, multivariate Cox-regression analysis revealed preoperative suPAR serum levels as an independent prognostic factor in this setting. Additionally, elevated preoperative suPAR but not creatinine levels were a predictor of acute kidney injury after CRLM resection, correlating with a longer postoperative hospitalization. Conclusions: Serum levels of suPAR represent a promising novel biomarker in patients with resectable CRLM that might help to guide preoperative treatment decisions with regards to patients’ outcome and the identification of patients particularly susceptible to postoperative acute kidney injury.

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