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Soluble programmed death-ligand 1 as a prognostic biomarker for overall survival in patients with diffuse large B-cell lymphoma: a replication study and combined analysis of 508 patients

Leukemia volume 31, pages 988–991 (2017)Cite this article

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Diffuse large B-cell lymphoma (DLBCL) is an aggressive hematologic malignancy with more than two-thirds of the patients cured with first-line rituximab-based treatments. However, relapsing or refractory patients have a very poor survival despite salvage therapies.1 The PD-1/PD-L1 pathway plays a major role in peripheral tolerance and homeostasis by inhibiting T-cell activation. By expressing PD-L1 on their surface, the tumor cells as well as some non-malignant cells from the tumor microenvironment co-opt the immune checkpoint pathways to evade immune destruction.2 Immunotherapies targeting the PD-1/PD-L1 pathway have recently shown remarkable clinical benefit in subsets of solid cancer patients3 and in DLBCL patients undergoing autologous stemcell transplant.4 Novel prognostic biomarkers are necessary to better identify the patients who would benefit the most from immunotherapy. We recently reported that the soluble PD-L1 protein expression (sPD-L1) was significantly increased in the blood of DLBCL patients versus healthy controls, and that elevated sPD-L1 was prognostic for overall survival (OS).5 Here, we confirmed these initial findings in an independent cohort of newly diagnosed DLBCL patients, evaluated tumor/microenvironment expression, and investigated the prognostic relevance of sPD-L1 on risk-stratified DLBCL patients when compared against established clinical, biological and molecular prognostic markers.

The previously published discovery cohort consisted of 283 newly diagnosed aggressive DLBCL patients, aged 18 to 60 years, from the French GOELAMS 075 multicenter randomized clinical trial (Supplementary Tables S1 and S2). The patients were treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) (51%) or R-CEEP/auto (49%). The five-year OS was estimated at 81.7% (95% confidence interval (CI) 77.3–86.4). There was no OS difference between the two arms of treatment. The replication cohort consisted of 225 de novo DLBCL patients, aged 18 to 92 years, all stages, from a prospective, observational cohort from the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence (SPORE).6 The patients were treated by R-CHOP (84%) or R-CHOP-like (16%) treatments. The 5-year OS estimate was 77.6% (95% CI 72.1–83.5). The matched control groups consisted of 60 French subjects and 98 US subjects, respectively. Plasma samples were collected pre-treatment using P100 tubes for the French study and EDTA tubes for the US study, and stored at −80 °C. The sPD-L1 production was measured in Rennes, France, for both cohorts using the enzyme-linked immunosorbent assay (PDCD1LG1 ELISA kit, USCN Life Science Inc., Wuhan, China), according to the manufacturer instructions (Supplementary Materials and Methods).

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Acknowledgements

This study is supported by the French Health Minister (BMS_LyTrans project; NCT01287923), the National Institute of Cancer (INCa Translational Research 2010), the French Lymphoma Study Association (LYSA), the French National Agency for Research (ANR Carnot/CALYM), the National Cancer Institute (P50 CA97274, R01 CA92153) and the Henry J Predolin Foundation. Concerning the French cohort, we are indebted to the LYSA pathology platform (Hôpital Henri Mondor, Créteil) for immunohistochemical experiments, and the Centre de Ressources Biologiques CRB-Santé (BB-0033-00056) of the Rennes hospital for providing high-quality samples. This work was partly supported by a French National Cancer Institute post-doctoral fellowship (grant number PDOC-RC-GO/07-003) to the first author (DR).

Author contributions

TF raised the fund. IA did the sPD-L1 measurements. DR did the data analysis. MJM and JRC contributed to the statistics. DR, JRC and TF did the data interpretation and wrote the manuscript. NM designed the parent French study. JRC designed the US study. GL and MP did the French database update and immunohistochemistry. ALF did the immunohistochemistry on the MER cohort. CP did the blood sample collection. IA, ALF, MJM, CP, TMH, SMA, BKL, KT, TEW, TL, SLS, MR and NM contributed to the writing and approving of the manuscript.

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Author notes

  1. D Rossille and I Azzaoui: Co-first authors.

  2. J R Cerhan and T Fest: Co-senior authors.

Authors and Affiliations

  1. UMR U1236, Université de Rennes 1, INSERM, EFS, Rennes, France

    D Rossille, I Azzaoui, C Pangault, K Tarte, T Lamy, M Roussel & T Fest

  2. Laboratoire d'hématologie, Pôle biologie, FHU CAMIn, CHU Rennes, Rennes, France

    D Rossille, I Azzaoui, C Pangault, K Tarte, T Lamy, M Roussel & T Fest

  3. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    A L Feldman

  4. Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA

    M J Maurer, S L Slager & J R Cerhan

  5. Département d'hématologie, CHU Bordeaux, Université, Bordeaux, France

    G Labouré, M Parrens & N Milpied

  6. Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA

    T M Habermann, S M Ansell & T E Witzig

  7. Department of Internal Medicine, University of Iowa, Iowa City, IA, USA

    B K Link

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  1. D Rossille
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Correspondence to T Fest.

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Rossille, D., Azzaoui, I., Feldman, A. et al. Soluble programmed death-ligand 1 as a prognostic biomarker for overall survival in patients with diffuse large B-cell lymphoma: a replication study and combined analysis of 508 patients. Leukemia 31, 988–991 (2017). https://doi.org/10.1038/leu.2016.385

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