TY - JOUR
T1 - Serum CD73 is a prognostic factor in patients with metastatic melanoma and is associated with response to anti-PD-1 therapy
AU - Turiello, Roberta
AU - Capone, Mariaelena
AU - Giannarelli, Diana
AU - Morretta, Elva
AU - Monti, Maria Chiara
AU - Madonna, Gabriele
AU - Mallardo, Domenico
AU - Festino, Lucia
AU - Azzaro, Rosa
AU - Levesque, Mitchell P.
AU - Imhof, Laurence
AU - Weide, Benjamin
AU - Amaral, Teresa
AU - Chevrier, Marc
AU - Sucker, Antje
AU - Rutkowski, Piotr
AU - Schadendorf, Dirk
AU - Lebbe, Celeste
AU - Luke, Jason John
AU - Wistuba-Hamprecht, Kilian
AU - Dummer, Reinhard
AU - Pinto, Aldo
AU - Morello, Silvana
AU - Ascierto, Paolo A.
N1 - Funding Information:
This work was supported by POR Campania FESR 2007-2013-O.O. 2.1-OCKEY (SM) and Italian Ministry of Health (IT-MOH) through "Ricerca Corrente" M2/M (PAA). GM has been founded by Istitutional "Ricerca Corrente". KWH and BW received funding from the Klaus Tschira Foundation (00.316.2017) for the T?bingen blood bank. KWH received funding for a 'junior research group' from the Medical Faculty of the University of T?bingen (2509-0-0).
Publisher Copyright:
©
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/12/23
Y1 - 2020/12/23
N2 - 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.
AB - 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.
KW - immunotherapy
KW - melanoma
KW - tumor biomarkers
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U2 - 10.1136/jitc-2020-001689
DO - 10.1136/jitc-2020-001689
M3 - Article
AN - SCOPUS:85098324718
VL - 8
JO - Journal for ImmunoTherapy of Cancer
JF - Journal for ImmunoTherapy of Cancer
SN - 2051-1426
IS - 2
M1 - e001689
ER -