Mesenchymal Stem Cells Promote Metastasis of Lung Cancer Cells by Downregulating Systemic Antitumor Immune Response

Marina Gazdic,Nebojsa Arsenijevic,Maja Misirkic-Marjanovic,Nemanja Jovicic,Bojana Simovic Markovic,Valentin Djonov,Miodrag L Lukic,Vladislav Volarevic,Vladimir Jakovljevic

doi:10.1155/2017/6294717

Marina Gazdic, Nebojsa Arsenijevic + Show 7 more

Open Access

https://doi.org/10.1155/2017/6294717

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Abstract

Since majority of systemically administered mesenchymal stem cells (MSCs) become entrapped within the lungs, we used metastatic model of lung cancer, induced by intravenous injection of Lewis lung cancer 1 (LLC1) cells, to investigate the molecular mechanisms involved in MSC-mediated modulation of metastasis. MSCs significantly augmented lung cancer metastasis, attenuate concentrations of proinflammatory cytokines (TNF-α, IL-17), and increase levels of immunosuppressive IL-10, nitric oxide, and kynurenine in sera of LLC1-treated mice. MSCs profoundly reduced infiltration of macrophages, TNF-α-producing dendritic cells (DCs), TNF-α-, and IL-17-producing CD4+ T cells but increased IL-10-producing CD4+ T lymphocytes in the lungs of tumor-bearing animals. The total number of lung-infiltrated, cytotoxic FasL, perforin-expressing, TNF-α-, and IL-17-producing CD8+ T lymphocytes, and NKG2D-expressing natural killer (NK) cells was significantly reduced in LLC1 + MSC-treated mice. Cytotoxicity of NK cells was suppressed by MSC-conditioned medium. This phenomenon was abrogated by the inhibitors of inducible nitric oxide synthase (iNOS) and indoleamine 2,3-dioxygenase (IDO), suggesting the importance of iNOS and IDO for MSC-mediated suppression of antitumor cytotoxicity of NK cells. This study provides the evidence that MSCs promote lung cancer metastasis by suppressing antitumor immune response raising concerns regarding safety of MSC-based therapy in patients who have genetic susceptibility for malignant diseases.

Highlights

Mesenchymal stem cells (MSCs) are self-renewable adult stem cells with fibroblast-like morphology that can be found in almost all postnatal tissues [1]
We showed that intravenous application of MSCs in tumor-bearing mice significantly suppressed systemic antitumor immune response, reduced total number of lung-infiltrated dendritic cells (DCs), macrophages, CD4+ T lymphocytes, CTLs, and natural killer (NK) cells, and attenuated antitumor cytotoxicity of CTLs and NK cells resulting with the expansion of metastatic lesions in the lungs
We investigated whether systemic application of MSCs could modulate spontaneous Lewis lung cancer 1 (LLC1) tumor cell metastasis to the lungs

Summary

Introduction

Mesenchymal stem cells (MSCs) are self-renewable adult stem cells with fibroblast-like morphology that can be found in almost all postnatal tissues [1]. MSCs are currently used in broad number of clinical trials due to their multilineage differentiation potential and immunomodulatory characteristics. Stem Cells International alternative activation of macrophages, and reducing proliferation, activation, and effector function of B and T lymphocytes, natural killer (NK), and natural killer T (NKT) cells [1]. The primary concern was the potential malignant transformation of the administered MSCs. A recent meta-analysis partly reassured the scientific community by showing that malignancies which were noticed in MSC-treated patients occurred only in patients with previous or current malignancies, with no formation of de novo tumors [4]. Potential of MSCs to promote neovascularization and suppress antitumor immunity is still existing as major concerns regarding the safety of MSC-based therapy and should be further explored in preclinical and clinical studies

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