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, 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.

Informations de copyright

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Déclaration de conflit d'intérêts

Competing interests: PAA has/had a consultant/advisory role for Bristol Myers-Squibb, Roche-Genentech, Merck Sharp & Dohme, Array, Novartis, Amgen, Merck Serono, Pierre Fabre, Incyte, NewLink Genetics, Genmab, Medimmune. He also received research funds from Bristol Myers-Squibb, Roche-Genentech, Array. KWH received commercial research grants from the Catalym GmbH and travel support from SITC (Society for Immunotherapy of Cancer). TA reports personal fees and travel grants from BMS, grants, personal fees and travel grants from Novartis, personal fees from Pierre Fabre, grants from Neracare, grants from Sanofi, outside the submitted work. RD has intermittent, project-focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator outside the submitted work. MPL intermittent project focused funding outside of the scope of the current work. LI intermittent project focused consulting and/or advisory relationship with Galderma outside the submitted work. DS reported consulting or advisory role for Roche/Genentech, Novartis, Bristol-Myers Squibb, MSD, Merck Serono, Amgen, Immunocore, Incyte, InFlarX, 4SC, Pierre Fabre, Mologen, Nektar, and Sanofi/Regeneron; honoraria from Roche/Genentech, Novartis, MSD, Bristol-Myers Squibb, Merck Serono, Amgen, Immunocore, Incyte, 4SC, Pierre Fabre, Array BioPharma, Pfizer, Philogen, and Regeneron; travel, accommodation and expenses from Roche/Genentech, Novartis, Bristol-Myers Squibb, Merck Serono, Amgen and Merck; speakers bureau for Novartis, Bristol-Myers Squibb, MSD, Pierre Fabre and Roche; research funding from Novartis and Bristol-Myers Squibb; steering committee member for Novartis, MSD and Bristol-Myers Squibb. PR has received honoraria for lectures and advisory boards from MSD, BMS, Novartis, Pierre Fabre, Amgen, Sanofi, Merck, Blueprint Medicines. JJL, Scientific Advisory Board: 7 Hills, Actym, Alphamab Oncology, Arch Oncology, Kanaph, Mavu, Onc. AI, Pyxis, Spring bank, Tempest; Consultancy: Abbvie, Algios, Array, Bayer, Bristol-Myers Squibb, Cstone, Eisai, EMD Serono, Janssen, Merck, Mersana, Novartis, PTx, RefleXion, Regeneron, Rubius, Silicon, Tesaro, Xilios; research support: (all to institution for clinical trials unless noted) AbbVie, Agios (IIT), Array (IIT), Astellas, Bristol-Myers Squibb, Corvus, EMD Serono, Immatics, Incyte, Kadmon, Macrogenics, Merck, Spring bank, Tizona, Xencor; travel: Bristol-Myers Squibb, EMD Serono, Janssen, Merck, Mersana, Pyxis; patents: (both provisional) Serial #15/612,657 (Cancer Immunotherapy), PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof). The other authors declare no potential competing interests.