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

Nikolaus B Wagner,Benjamin Weide,Mirko Gries,Maike Reith,Claus Garbe,Viktor Umansky,Valerie Schuermans,Christoffer Gebhardt,Dirk Schadendorf,Charlotte Kemper,Jochen Utikal,Ramtin Lichtenberger,Kathrin Tarnanidis,Coretta Kehrel,Esther Herpel,Tim Holland-Letz,Antje Sucker,Anne Funder

doi:10.1186/s40425-019-0828-1

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.

Highlights

Predicting metastasis in melanoma patients is important for disease management and could help to identify those who might benefit from adjuvant treatment
The aims of this study were to investigate (i) whether S100A8/A9 expression in tissue sections of primary melanomas and melanoma metastases discriminates between short-term and long-term survivors, (ii) whether elevated serum S100A8/A9 is associated with impaired survival of stage III and IV melanoma patients, and (iii) whether elevated serum S100A8/A9 is associated with survival of melanoma patients treated with the anti-Programmed cell death protein 1 (PD-1) immune checkpoint inhibitor pembrolizumab
S100A8/A9 expression in tissue is increased in metastatic melanoma and in primary melanomas and melanoma metastases of short-term survivors Immunofluorescence analysis of S100A8/A9 expression in tissue sections of primary melanomas revealed an exclusive and abundant expression of S100A8/A9 in cells of the tumor microenvironment (TME), mainly granulocytes, whereas S100B expression was restricted to melanoma cells (Fig. 1a and b)

Summary

Introduction

Predicting 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, in the setting of immunotherapy. Certain cell types present within the tumor microenvironment (TME) such as myeloid cells (macrophages, neutrophils, eosinophils, monocytes, and myeloidderived suppressor cells [MDSCs]) have been identified to serve as prognostic markers in melanoma [5, 6]. Since S100A8/A9 is produced by melanomaassociated immune cells and relates to tumor aggressiveness and progression [6, 9, 13], changes in its levels in melanoma patients over the clinical course might reflect individual immune responses and could be useful as novel biomarkers predicting progression or response to treatment

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