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Tumor microenvironment-derived S100A8/A9 is a novel prognostic biomarker for advanced melanoma patients and during immunotherapy with anti-PD-1 antibodies

Authors
  • Wagner, Nikolaus B.1, 2, 3, 4
  • Weide, Benjamin3
  • Gries, Mirko1, 2
  • Reith, Maike1, 2
  • Tarnanidis, Kathrin1, 2
  • Schuermans, Valerie1, 2
  • Kemper, Charlotte1, 2
  • Kehrel, Coretta1, 2
  • Funder, Anne1, 2
  • Lichtenberger, Ramtin1, 2
  • Sucker, Antje5
  • Herpel, Esther6, 7
  • Holland-Letz, Tim8
  • Schadendorf, Dirk5
  • Garbe, Claus3
  • Umansky, Viktor1, 2
  • Utikal, Jochen1, 2
  • Gebhardt, Christoffer1, 2, 9
  • 1 Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany , Heidelberg (Germany)
  • 2 University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany , Mannheim (Germany)
  • 3 University Hospital Tuebingen, Tuebingen, Germany , Tuebingen (Germany)
  • 4 Cantonal Hospital St. Gallen, Rorschacher Strasse 95, St. Gallen, 9007, Switzerland , St. Gallen (Switzerland)
  • 5 University Hospital Essen, Essen, Germany , Essen (Germany)
  • 6 NCT Tissue Bank, National Center of Tumor Diseases (NCT), Heidelberg, Germany , Heidelberg (Germany)
  • 7 University Hospital Heidelberg, Heidelberg, Germany , Heidelberg (Germany)
  • 8 German Cancer Research Center (DKFZ), Heidelberg, Germany , Heidelberg (Germany)
  • 9 University Hospital Hamburg-Eppendorf (UKE), Hamburg, Germany , Hamburg (Germany)
Type
Published Article
Journal
Journal for ImmunoTherapy of Cancer
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Dec 05, 2019
Volume
7
Issue
1
Identifiers
DOI: 10.1186/s40425-019-0828-1
Source
Springer Nature
Keywords
License
Green

Abstract

BackgroundPredicting metastasis in melanoma patients is important for disease management and could help to identify those who might benefit from adjuvant treatment. The aim of this study was to investigate whether the tumor microenvironment-derived protein S100A8/A9 qualifies as prognostic marker for melanoma patients, also in the setting of immunotherapy.MethodsS100A8/A9 gene and protein expression were analyzed on melanocytic nevi, primary melanomas and metastases using a cDNA library and three independent tissue-microarrays (TMA). Serum levels of S100A8/A9 were measured using a specific ELISA in two independent cohorts of 354 stage III and stage IV melanoma patients as well as in two independent cohorts of patients treated with the PD-1 antibody pembrolizumab.ResultscDNA analysis revealed an upregulation of S100A8 and S100A9 gene expression in melanoma metastases compared to primary melanomas. Significantly higher numbers of infiltrating S100A8/A9 positive cells were found in tissue samples of metastasizing primary melanomas compared to non-metastasizing melanomas (P < .0001) and in melanomas of short-term survivors compared to long-term survivors (P < .0001). Serum S100A8/A9 levels > 5.5 mg/l were associated with impaired overall survival in two independent cohorts (both P < .0001). Importantly, patients with serum elevated S100A8/A9 treated with pembrolizumab showed significantly impaired survival compared to patients with lower S100A8/A9 levels (cohort 1: P = .0051; cohort 2: P < .0001).ConclusionsThe tumor microenvironment-associated protein S100A8/A9 serves as a novel prognostic marker for metastasis and survival of metastatic melanoma patients and predicts response to immunotherapy with pembrolizumab. These data underscore the significance of tumor microenvironment-derived factors as suitable biomarkers for melanoma.

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