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The Effects of Mesenchymal Stem Cells on Antimelanoma Immunity Depend on the Timing of Their Administration

There is still a lively debate about whether mesenchymal stem cells (MSCs) promote or suppress antitumor immune response. Although several possible explanations have been proposed, including different numbers of injected and engrafted MSCs, heterogeneity in phenotype, and function of tumor cells, th...

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Autores principales: Miloradovic, Dragana, Miloradovic, Dragica, Markovic, Bojana Simovic, Acovic, Aleksandar, Harrell, Carl Randall, Djonov, Valentin, Arsenijevic, Nebojsa, Volarevic, Vladislav
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368936/
https://www.ncbi.nlm.nih.gov/pubmed/32695181
http://dx.doi.org/10.1155/2020/8842659
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author Miloradovic, Dragana
Miloradovic, Dragica
Markovic, Bojana Simovic
Acovic, Aleksandar
Harrell, Carl Randall
Djonov, Valentin
Arsenijevic, Nebojsa
Volarevic, Vladislav
author_facet Miloradovic, Dragana
Miloradovic, Dragica
Markovic, Bojana Simovic
Acovic, Aleksandar
Harrell, Carl Randall
Djonov, Valentin
Arsenijevic, Nebojsa
Volarevic, Vladislav
author_sort Miloradovic, Dragana
collection PubMed
description There is still a lively debate about whether mesenchymal stem cells (MSCs) promote or suppress antitumor immune response. Although several possible explanations have been proposed, including different numbers of injected and engrafted MSCs, heterogeneity in phenotype, and function of tumor cells, the exact molecular mechanisms responsible for opposite effects of MSCs in modulation of antitumor immunity are still unknown. Herewith, we used a B16F10 murine melanoma model to investigate whether timing of MSC administration in tumor-bearing mice was crucially important for their effects on antitumor immunity. MSCs, intravenously injected 24 h after melanoma induction (B16F10+MSC(1d)-treated mice), significantly enhanced natural killer (NK) and T cell-driven antitumor immunity, suppressed tumor growth, and improved survival of melanoma-bearing animals. Significantly higher plasma levels of antitumorigenic cytokines (TNF-α and IFN-γ), remarkably lower plasma levels of immunosuppressive cytokines (TGF-β and IL-10), and a significantly higher number of tumor-infiltrating, IFN-γ-producing, FasL- and granzyme B-expressing NK cells, IL-17-producing CD4+Th17 cells, IFN-γ- and TNF-α-producing CD4+Th1 cells, and CD8+cytotoxic T lymphocytes (CTLs) were observed in B16F10+MSC(1d)-treated mice. On the contrary, MSCs, injected 14 days after melanoma induction (B16F10+MSC(14d)-treated mice), promoted tumor growth by suppressing antigen-presenting properties of tumor-infiltrating dendritic cells (DCs) and macrophages and by reducing tumoricidal capacity of NK cells and T lymphocytes. Significantly higher plasma levels of TGF-β and IL-10, remarkably lower plasma levels of TNF-α and IFN-γ, and significantly reduced number of tumor-infiltrating, I-A-expressing, and IL-12-producing macrophages, CD80- and I-A-expressing DCs, granzyme B-expressing CTLs and NK cells, IFN-γ- and IL-17-producing CTLs, CD4+Th1, and Th17 cells were observed in B16F10+MSC(14d)-treated animals. In summing up, the timing of MSC administration into the tumor microenvironment was crucially important for MSC-dependent modulation of antimelanoma immunity. MSCs transplanted during the initial phase of melanoma growth exerted tumor-suppressive effect, while MSCs injected during the progressive stage of melanoma development suppressed antitumor immunity and enhanced tumor expansion.
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spelling pubmed-73689362020-07-20 The Effects of Mesenchymal Stem Cells on Antimelanoma Immunity Depend on the Timing of Their Administration Miloradovic, Dragana Miloradovic, Dragica Markovic, Bojana Simovic Acovic, Aleksandar Harrell, Carl Randall Djonov, Valentin Arsenijevic, Nebojsa Volarevic, Vladislav Stem Cells Int Research Article There is still a lively debate about whether mesenchymal stem cells (MSCs) promote or suppress antitumor immune response. Although several possible explanations have been proposed, including different numbers of injected and engrafted MSCs, heterogeneity in phenotype, and function of tumor cells, the exact molecular mechanisms responsible for opposite effects of MSCs in modulation of antitumor immunity are still unknown. Herewith, we used a B16F10 murine melanoma model to investigate whether timing of MSC administration in tumor-bearing mice was crucially important for their effects on antitumor immunity. MSCs, intravenously injected 24 h after melanoma induction (B16F10+MSC(1d)-treated mice), significantly enhanced natural killer (NK) and T cell-driven antitumor immunity, suppressed tumor growth, and improved survival of melanoma-bearing animals. Significantly higher plasma levels of antitumorigenic cytokines (TNF-α and IFN-γ), remarkably lower plasma levels of immunosuppressive cytokines (TGF-β and IL-10), and a significantly higher number of tumor-infiltrating, IFN-γ-producing, FasL- and granzyme B-expressing NK cells, IL-17-producing CD4+Th17 cells, IFN-γ- and TNF-α-producing CD4+Th1 cells, and CD8+cytotoxic T lymphocytes (CTLs) were observed in B16F10+MSC(1d)-treated mice. On the contrary, MSCs, injected 14 days after melanoma induction (B16F10+MSC(14d)-treated mice), promoted tumor growth by suppressing antigen-presenting properties of tumor-infiltrating dendritic cells (DCs) and macrophages and by reducing tumoricidal capacity of NK cells and T lymphocytes. Significantly higher plasma levels of TGF-β and IL-10, remarkably lower plasma levels of TNF-α and IFN-γ, and significantly reduced number of tumor-infiltrating, I-A-expressing, and IL-12-producing macrophages, CD80- and I-A-expressing DCs, granzyme B-expressing CTLs and NK cells, IFN-γ- and IL-17-producing CTLs, CD4+Th1, and Th17 cells were observed in B16F10+MSC(14d)-treated animals. In summing up, the timing of MSC administration into the tumor microenvironment was crucially important for MSC-dependent modulation of antimelanoma immunity. MSCs transplanted during the initial phase of melanoma growth exerted tumor-suppressive effect, while MSCs injected during the progressive stage of melanoma development suppressed antitumor immunity and enhanced tumor expansion. Hindawi 2020-07-10 /pmc/articles/PMC7368936/ /pubmed/32695181 http://dx.doi.org/10.1155/2020/8842659 Text en Copyright © 2020 Dragana Miloradovic et al. http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Miloradovic, Dragana
Miloradovic, Dragica
Markovic, Bojana Simovic
Acovic, Aleksandar
Harrell, Carl Randall
Djonov, Valentin
Arsenijevic, Nebojsa
Volarevic, Vladislav
The Effects of Mesenchymal Stem Cells on Antimelanoma Immunity Depend on the Timing of Their Administration
title The Effects of Mesenchymal Stem Cells on Antimelanoma Immunity Depend on the Timing of Their Administration
title_full The Effects of Mesenchymal Stem Cells on Antimelanoma Immunity Depend on the Timing of Their Administration
title_fullStr The Effects of Mesenchymal Stem Cells on Antimelanoma Immunity Depend on the Timing of Their Administration
title_full_unstemmed The Effects of Mesenchymal Stem Cells on Antimelanoma Immunity Depend on the Timing of Their Administration
title_short The Effects of Mesenchymal Stem Cells on Antimelanoma Immunity Depend on the Timing of Their Administration
title_sort effects of mesenchymal stem cells on antimelanoma immunity depend on the timing of their administration
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368936/
https://www.ncbi.nlm.nih.gov/pubmed/32695181
http://dx.doi.org/10.1155/2020/8842659
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