Serum CD73 is a prognostic factor in patients with metastatic melanoma and is associated with response to anti-PD-1 therapy

Abstract

BackgroundInhibitors 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.MethodsSoluble 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.ResultsPatients 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).ConclusionOur 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.

Exosomal CD73 from serum of patients with melanoma suppresses lymphocyte functions and is associated with therapy resistance to anti-PD-1 agents

“…15 Interestingly, we have recently demonstrated the soluble form of CD73 as predictive peripheral blood biomarker of response to nivolumab or pembrolizumab in patients with metastatic melanoma. 21 The serum contains multiple forms of CD73: the soluble CD73 which derives from the cleavage of the cell-membrane anchored CD73, and a form expressed on exosomes. Importantly, it is known that cancer exosomes carry CD73, which is enzymatically active in producing adenosine.…”

“…To measure the activity of CD73 in purified exosomal samples, we evaluated the AMPase hydrolysis using multiple reaction monitoring mass spectrometry (MRM-MS), as described before. 21 A total of 5 µg of exosomes proteins in 50 µL total volume of PBS were incubated at 37°C for 10 min, and then treated or not with CD73 inhibitors for 30 min at 37°C. Specifically, we used 5' α,β-methylene-ADP (APCP; Sigma-Aldrich) (100 µM) or the anti-human CD73 mAb (Clone 7G2; Thermo Fisher Scientific) (5 µg/mL).…”

Potential roles of serum ATPase and AMPase in predicting diagnosis of colorectal cancer patients

“…[ 29 ]. In some instances, enzymes involved in the hydrolysis of extracellular nucleotides have become reliable indicators for monitoring disease [ 30 , 31 ]. These enzymes include members of the ENTPD family, which hydrolyze ATP into AMP, and CD73, which hydrolyses AMP to adenosine [ 32 ].…”

Clinical Biomarkers for Early Identification of Patients with Intracranial Metastatic Disease

“…Several serum markers associated with melanoma survival or response to therapy, including lactate dehydrogenase and CD73, have been described, but few studies have successfully identified and validated serum or CSF markers of melanoma-associated IMD, which occurs in over 50% of melanoma patients [ 99 , 100 , 101 ]. The use of cytopathology to detect whole circulating melanoma cells in CSF has been described in the diagnosis of leptomeningeal disease; however, the application of this technique may be limited by its specificity, as patients without circulating melanoma cells may have IMD [ 102 ].…”