Tumour stromal cells derived from paediatric malignancies display MSC-like properties and impair NK cell cytotoxicity

Pascal-David Johann,Philippa Mang,Friederike Gieseke,Rupert Handgretinger,Sorin Armeanu-Ebinger,Martin Vaegler,Torsten Kluba,Ingo Müller

doi:10.1186/1471-2407-10-501

Abstract

BackgroundTumour growth and metastatic infiltration are favoured by several components of the tumour microenvironment. Bone marrow-derived multipotent mesenchymal stromal cells (MSC) are known to contribute to the tumour stroma. When isolated from healthy bone marrow, MSC exert potent antiproliferative effects on immune effector cells. Due to phenotypic and morphological similarities of MSC and tumour stromal cells (TStrC), we speculated that immunotherapeutic approaches may be hampered if TStrC may still exhibit immunomodulatory properties of MSC.MethodsIn order to compare immunomodulatory properties of MSC and tumour stromal cells (TStrC), we established and analyzed TStrC cultures from eleven paediatric tumours and MSC preparations from bone marrow aspirates. Immunophenotyping, proliferation assays and NK cell cytotoxicity assays were employed to address the issue.ResultsWhile TStrC differed from MSC in terms of plasticity, they shared surface expression of CD105, CD73 and other markers used for MSC characterization. Furthermore, TStrC displayed a strong antiproliferative effect on peripheral blood mononuclear cells (PBMC) in coculture experiments similar to MSC. NK cell cytotoxicity was significantly impaired after co-culture with TStrC and expression of the activating NK cell receptors NKp44 and NKp46 was reduced.ConclusionsOur data show that TStrC and MSC share important phenotypic and functional characteristics. The inhibitory effect of TStrC on PBMC and especially on NK cells may facilitate the immune evasion of paediatric tumours.

Highlights

Tumour growth and metastatic infiltration are favoured by several components of the tumour microenvironment
Establishment and characterisation of primary tumourstromal cell cultures tumour stromal cells (TStrC) were isolated from eleven paediatric tumours (Table 1)
Cells could be successfully propagated under culture conditions used for bone marrow-derived mesenchymal stromal cells (MSC) [20]

Summary

Introduction

Tumour growth and metastatic infiltration are favoured by several components of the tumour microenvironment. Bone marrow-derived multipotent mesenchymal stromal cells (MSC) are known to contribute to the tumour stroma. They modulate functions of B cells and of dendritic cells [12] and, importantly, MSC do inhibit the proliferation of NK cells and suppress their cytotoxic activity [13,14,15] These immunological properties may contribute to tumour spread as MSC can be found in human breast cancers and promote metastasis [16]. Bioluminescence imaging of mice indicated a tropism of bone marrow-derived MSC to inflammatory microenvironments such as tumours [17] In this context, the inhibitory effects of MSC on virtually all cells of the immune system may be relevant [12]. This may be one mechanism to inhibit lysis of e. g. neuroblastoma cells, which are known to express only low densities of HLA molecules and represent good NK cell targets [18]

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Results

Conclusion