Serum CD73 is a prognostic factor in patients with metastatic melanoma and is associated with response to anti-PD-1 therapy
Background Inhibitors of immune checkpoint programmed cell death protein 1 (PD-1) receptor on T cells have shown remarkable clinical outcomes in metastatic melanoma. However, most patients are resistant to therapy. Production of extracellular adenosine, via CD73-mediated catabolism of AMP, contribut...
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BMJ Publishing Group
2020-10-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/2/e001689.full |
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| author | Dirk Schadendorf Celeste Lebbe Teresa Amaral Benjamin Weide Mariaelena Capone Gabriele Madonna Lucia Festino Reinhard Dummer Domenico Mallardo Paolo A Ascierto Piotr Rutkowski Jason John Luke Kilian Wistuba-Hamprecht Mitchell P Levesque Roberta Turiello Elva Morretta Maria Chiara Monti Rosa Azzaro Laurence Imhof Marc Chevrier Antje Sucker Aldo Pinto Silvana Morello |
| author_facet | Dirk Schadendorf Celeste Lebbe Teresa Amaral Benjamin Weide Mariaelena Capone Gabriele Madonna Lucia Festino Reinhard Dummer Domenico Mallardo Paolo A Ascierto Piotr Rutkowski Jason John Luke Kilian Wistuba-Hamprecht Mitchell P Levesque Roberta Turiello Elva Morretta Maria Chiara Monti Rosa Azzaro Laurence Imhof Marc Chevrier Antje Sucker Aldo Pinto Silvana Morello |
| author_sort | Dirk Schadendorf |
| collection | DOAJ |
| description | Background Inhibitors of immune checkpoint programmed cell death protein 1 (PD-1) receptor on T cells have shown remarkable clinical outcomes in metastatic melanoma. However, most patients are resistant to therapy. Production of extracellular adenosine, via CD73-mediated catabolism of AMP, contributes to suppress T-cell-mediated responses against cancer. In this study, we analyzed the expression and activity of soluble CD73 in sera of patients with melanoma undergoing anti-PD-1± cytotoxic T-lymphocyte-associated antigen 4 therapy.Methods Soluble CD73 expression and activity were retrospectively analyzed in serum of a total of 546 patients with melanoma from different centers before starting treatment (baseline) with anti-PD-1 agents, nivolumab or pembrolizumab, and compared with those of 96 healthy subjects. The CD73 activity was correlated with therapy response and survival of patients.Results Patients with melanoma show significantly higher CD73 activity and expression than those observed in healthy donors (p<0.0001). Elevated pretreatment levels of CD73 activity were associated with non-response to therapy with nivolumab or pembrolizumab. During treatment, levels of soluble CD73 activity remain unchanged from baseline and still stratify clinical responders from non-responders. High levels of serum CD73 enzymatic activity associate with reduced overall survival (OS; HR=1.36, 95% CI 1.03 to 1.78; p=0.03) as well as progression-free survival (PFS; HR=1.42, 95% CI 1.13 to 1.79, p=0.003). Further, the multivariate Cox regression analysis indicates that serum CD73 activity is an independent prognostic factor besides serum lactate dehydrogenase levels and the presence of brain metastases for both OS (p=0.009) and PFS (p=0.001).Conclusion Our data indicate the relevance of serum CD73 in patients with advanced melanoma receiving anti-PD-1 therapy and support further investigation on targeting CD73 in combination with anti-PD-1 antibodies. |
| format | Article |
| id | doaj-art-ca411bc46b9f4db2a7c3cf284f8adfd0 |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-10-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-ca411bc46b9f4db2a7c3cf284f8adfd02025-08-20T02:13:20ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-10-018210.1136/jitc-2020-001689Serum CD73 is a prognostic factor in patients with metastatic melanoma and is associated with response to anti-PD-1 therapyDirk Schadendorf0Celeste Lebbe1Teresa Amaral2Benjamin Weide3Mariaelena Capone4Gabriele Madonna5Lucia Festino6Reinhard Dummer7Domenico Mallardo8Paolo A Ascierto9Piotr Rutkowski10Jason John Luke11Kilian Wistuba-Hamprecht12Mitchell P Levesque13Roberta Turiello14Elva Morretta15Maria Chiara Monti16Rosa Azzaro17Laurence Imhof18Marc Chevrier19Antje Sucker20Aldo Pinto21Silvana Morello22University Hospital of Essen, University Duisburg-Essen, NCT-West, Essen Campus, German Cancer Consortium, Partner Site Essen & University Alliance Ruhr, One Health Research Centre, Essen, Germany21 Dermatology, Hopital Saint-Louis, Paris, Île-de-France, FranceDepartment of Dermatology, University Hospital Tübingen, Eberhard Karls University of Tübingen, Tübingen, GermanyDepartment of Dermatology, University Hospital Tübingen, Eberhard Karls University of Tübingen, Tübingen, Germany2Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, Italy2Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, Italy1Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, ItalyDepartment of Dermatology, University Hospital of Zurich, Zurich, Switzerland1Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, ItalyMelanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, ItalyDepartment of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, PolandUPMC Hillman Cancer Center and University of Pittsburgh, Pittsburgh, Pennsylvania, USADepartment of Dermatology, University Hospital Tübingen, Eberhard Karls University of Tübingen, Tübingen, Germany5 Dermatology, University Hospital Zurich, Zurich, SwitzerlandDepartment of Pharmacy, University of Salerno, Fisciano, ItalyDepartment of Pharmacy, University of Salerno, Fisciano, ItalyDepartment of Pharmacy, University of Salerno, Fisciano, ItalyIstituto Nazionale Tumori IRCCS Fondazione G Pascale, Napoli, Italy5 Dermatology, University Hospital Zurich, Zurich, Switzerland1Janssen Research and Development, LLC, Spring House, United States of America8 Dermatology, University Hospital Essen, Essen, Nordrhein-Westfalen, Germany1 Pharmacy, University of Salerno, Fisciano, Campania, ItalyDepartment of Pharmacy, University of Salerno, Fisciano, ItalyBackground Inhibitors of immune checkpoint programmed cell death protein 1 (PD-1) receptor on T cells have shown remarkable clinical outcomes in metastatic melanoma. However, most patients are resistant to therapy. Production of extracellular adenosine, via CD73-mediated catabolism of AMP, contributes to suppress T-cell-mediated responses against cancer. In this study, we analyzed the expression and activity of soluble CD73 in sera of patients with melanoma undergoing anti-PD-1± cytotoxic T-lymphocyte-associated antigen 4 therapy.Methods Soluble CD73 expression and activity were retrospectively analyzed in serum of a total of 546 patients with melanoma from different centers before starting treatment (baseline) with anti-PD-1 agents, nivolumab or pembrolizumab, and compared with those of 96 healthy subjects. The CD73 activity was correlated with therapy response and survival of patients.Results Patients with melanoma show significantly higher CD73 activity and expression than those observed in healthy donors (p<0.0001). Elevated pretreatment levels of CD73 activity were associated with non-response to therapy with nivolumab or pembrolizumab. During treatment, levels of soluble CD73 activity remain unchanged from baseline and still stratify clinical responders from non-responders. High levels of serum CD73 enzymatic activity associate with reduced overall survival (OS; HR=1.36, 95% CI 1.03 to 1.78; p=0.03) as well as progression-free survival (PFS; HR=1.42, 95% CI 1.13 to 1.79, p=0.003). Further, the multivariate Cox regression analysis indicates that serum CD73 activity is an independent prognostic factor besides serum lactate dehydrogenase levels and the presence of brain metastases for both OS (p=0.009) and PFS (p=0.001).Conclusion Our data indicate the relevance of serum CD73 in patients with advanced melanoma receiving anti-PD-1 therapy and support further investigation on targeting CD73 in combination with anti-PD-1 antibodies.https://jitc.bmj.com/content/8/2/e001689.full |
| spellingShingle | Dirk Schadendorf Celeste Lebbe Teresa Amaral Benjamin Weide Mariaelena Capone Gabriele Madonna Lucia Festino Reinhard Dummer Domenico Mallardo Paolo A Ascierto Piotr Rutkowski Jason John Luke Kilian Wistuba-Hamprecht Mitchell P Levesque Roberta Turiello Elva Morretta Maria Chiara Monti Rosa Azzaro Laurence Imhof Marc Chevrier Antje Sucker Aldo Pinto Silvana Morello Serum CD73 is a prognostic factor in patients with metastatic melanoma and is associated with response to anti-PD-1 therapy Journal for ImmunoTherapy of Cancer |
| title | Serum CD73 is a prognostic factor in patients with metastatic melanoma and is associated with response to anti-PD-1 therapy |
| title_full | Serum CD73 is a prognostic factor in patients with metastatic melanoma and is associated with response to anti-PD-1 therapy |
| title_fullStr | Serum CD73 is a prognostic factor in patients with metastatic melanoma and is associated with response to anti-PD-1 therapy |
| title_full_unstemmed | Serum CD73 is a prognostic factor in patients with metastatic melanoma and is associated with response to anti-PD-1 therapy |
| title_short | Serum CD73 is a prognostic factor in patients with metastatic melanoma and is associated with response to anti-PD-1 therapy |
| title_sort | serum cd73 is a prognostic factor in patients with metastatic melanoma and is associated with response to anti pd 1 therapy |
| url | https://jitc.bmj.com/content/8/2/e001689.full |
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