Regional Hyperthermia Enhances Mesenchymal Stem Cell Recruitment to Tumor Stroma: Implications for Mesenchymal Stem Cell-Based Tumor Therapy

Mariella Tutter; Christina Schug; Kathrin A. Schmohl; Sarah Urnauer; Carolin Kitzberger; Nathalie Schwenk; Matteo Petrini; Christian Zach; Sibylle Ziegler; Peter Bartenstein; Wolfgang A. Weber; Gabriele Multhoff; Ernst Wagner; Lars H. Lindner; Peter J. Nelson; Christine Spitzweg

doi:10.1016/j.ymthe.2020.10.009

Regional Hyperthermia Enhances Mesenchymal Stem Cell Recruitment to Tumor Stroma: Implications for Mesenchymal Stem Cell-Based Tumor Therapy

Mariella Tutter, Christina Schug, Kathrin A. Schmohl, Sarah Urnauer, Carolin Kitzberger, Nathalie Schwenk, Matteo Petrini, Christian Zach, Sibylle Ziegler, Peter Bartenstein, Wolfgang A. Weber, Gabriele Multhoff, Ernst Wagner, Lars H. Lindner, Peter J. Nelson, Christine Spitzweg

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22 Scopus citations

Abstract

The tropism of mesenchymal stem cells (MSCs) for tumors forms the basis for their use as delivery vehicles for the tumor-specific transport of therapeutic genes, such as the theranostic sodium iodide symporter (NIS). Hyperthermia is used as an adjuvant for various tumor therapies and has been proposed to enhance leukocyte recruitment. Here, we describe the enhanced recruitment of adoptively applied NIS-expressing MSCs to tumors in response to regional hyperthermia. Hyperthermia (41°C, 1 h) of human hepatocellular carcinoma cells (HuH7) led to transiently increased production of immunomodulatory factors. MSCs showed enhanced chemotaxis to supernatants derived from heat-treated cells in a 3D live-cell tracking assay and was validated in vivo in subcutaneous HuH7 mouse xenografts. Cytomegalovirus (CMV)-NIS-MSCs were applied 6–48 h after or 24–48 h before hyperthermia treatment. Using ¹²³I-scintigraphy, thermo-stimulation (41°C, 1 h) 24 h after CMV-NIS-MSC injection resulted in a significantly increased uptake of ¹²³I in heat-treated tumors compared with controls. Immunohistochemical staining and real-time PCR confirmed tumor-selective, temperature-dependent MSC migration. Therapeutic efficacy was significantly enhanced by combining CMV-NIS-MSC-mediated ¹³¹I therapy with regional hyperthermia. We demonstrate here for the first time that hyperthermia can significantly boost tumoral MSC recruitment, thereby significantly enhancing therapeutic efficacy of MSC-mediated NIS gene therapy.

Original language	English
Pages (from-to)	788-803
Number of pages	16
Journal	Molecular Therapy
Volume	29
Issue number	2
DOIs	https://doi.org/10.1016/j.ymthe.2020.10.009
State	Published - 3 Feb 2021

Keywords

gene therapy
hepatocellular carcinoma
mesenchymal stem cells
regional hyperthermia
sodium iodide symporter

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10.1016/j.ymthe.2020.10.009

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Tutter, M., Schug, C., Schmohl, K. A., Urnauer, S., Kitzberger, C., Schwenk, N., Petrini, M., Zach, C., Ziegler, S., Bartenstein, P., Weber, W. A., Multhoff, G., Wagner, E., Lindner, L. H., Nelson, P. J., & Spitzweg, C. (2021). Regional Hyperthermia Enhances Mesenchymal Stem Cell Recruitment to Tumor Stroma: Implications for Mesenchymal Stem Cell-Based Tumor Therapy. Molecular Therapy, 29(2), 788-803. https://doi.org/10.1016/j.ymthe.2020.10.009

@article{33118fb26c004421835aa7222547e2cd,

title = "Regional Hyperthermia Enhances Mesenchymal Stem Cell Recruitment to Tumor Stroma: Implications for Mesenchymal Stem Cell-Based Tumor Therapy",

abstract = "The tropism of mesenchymal stem cells (MSCs) for tumors forms the basis for their use as delivery vehicles for the tumor-specific transport of therapeutic genes, such as the theranostic sodium iodide symporter (NIS). Hyperthermia is used as an adjuvant for various tumor therapies and has been proposed to enhance leukocyte recruitment. Here, we describe the enhanced recruitment of adoptively applied NIS-expressing MSCs to tumors in response to regional hyperthermia. Hyperthermia (41°C, 1 h) of human hepatocellular carcinoma cells (HuH7) led to transiently increased production of immunomodulatory factors. MSCs showed enhanced chemotaxis to supernatants derived from heat-treated cells in a 3D live-cell tracking assay and was validated in vivo in subcutaneous HuH7 mouse xenografts. Cytomegalovirus (CMV)-NIS-MSCs were applied 6–48 h after or 24–48 h before hyperthermia treatment. Using 123I-scintigraphy, thermo-stimulation (41°C, 1 h) 24 h after CMV-NIS-MSC injection resulted in a significantly increased uptake of 123I in heat-treated tumors compared with controls. Immunohistochemical staining and real-time PCR confirmed tumor-selective, temperature-dependent MSC migration. Therapeutic efficacy was significantly enhanced by combining CMV-NIS-MSC-mediated 131I therapy with regional hyperthermia. We demonstrate here for the first time that hyperthermia can significantly boost tumoral MSC recruitment, thereby significantly enhancing therapeutic efficacy of MSC-mediated NIS gene therapy.",

keywords = "gene therapy, hepatocellular carcinoma, mesenchymal stem cells, regional hyperthermia, sodium iodide symporter",

author = "Mariella Tutter and Christina Schug and Schmohl, {Kathrin A.} and Sarah Urnauer and Carolin Kitzberger and Nathalie Schwenk and Matteo Petrini and Christian Zach and Sibylle Ziegler and Peter Bartenstein and Weber, {Wolfgang A.} and Gabriele Multhoff and Ernst Wagner and Lindner, {Lars H.} and Nelson, {Peter J.} and Christine Spitzweg",

note = "Publisher Copyright: {\textcopyright} 2020 The American Society of Gene and Cell Therapy",

year = "2021",

month = feb,

day = "3",

doi = "10.1016/j.ymthe.2020.10.009",

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Tutter, M, Schug, C, Schmohl, KA, Urnauer, S, Kitzberger, C, Schwenk, N, Petrini, M, Zach, C, Ziegler, S, Bartenstein, P, Weber, WA , Multhoff, G, Wagner, E, Lindner, LH, Nelson, PJ & Spitzweg, C 2021, 'Regional Hyperthermia Enhances Mesenchymal Stem Cell Recruitment to Tumor Stroma: Implications for Mesenchymal Stem Cell-Based Tumor Therapy', Molecular Therapy, vol. 29, no. 2, pp. 788-803. https://doi.org/10.1016/j.ymthe.2020.10.009

TY - JOUR

T1 - Regional Hyperthermia Enhances Mesenchymal Stem Cell Recruitment to Tumor Stroma

T2 - Implications for Mesenchymal Stem Cell-Based Tumor Therapy

AU - Tutter, Mariella

AU - Schug, Christina

AU - Schmohl, Kathrin A.

AU - Urnauer, Sarah

AU - Kitzberger, Carolin

AU - Schwenk, Nathalie

AU - Petrini, Matteo

AU - Zach, Christian

AU - Ziegler, Sibylle

AU - Bartenstein, Peter

AU - Weber, Wolfgang A.

AU - Multhoff, Gabriele

AU - Wagner, Ernst

AU - Lindner, Lars H.

AU - Nelson, Peter J.

AU - Spitzweg, Christine

PY - 2021/2/3

Y1 - 2021/2/3

N2 - The tropism of mesenchymal stem cells (MSCs) for tumors forms the basis for their use as delivery vehicles for the tumor-specific transport of therapeutic genes, such as the theranostic sodium iodide symporter (NIS). Hyperthermia is used as an adjuvant for various tumor therapies and has been proposed to enhance leukocyte recruitment. Here, we describe the enhanced recruitment of adoptively applied NIS-expressing MSCs to tumors in response to regional hyperthermia. Hyperthermia (41°C, 1 h) of human hepatocellular carcinoma cells (HuH7) led to transiently increased production of immunomodulatory factors. MSCs showed enhanced chemotaxis to supernatants derived from heat-treated cells in a 3D live-cell tracking assay and was validated in vivo in subcutaneous HuH7 mouse xenografts. Cytomegalovirus (CMV)-NIS-MSCs were applied 6–48 h after or 24–48 h before hyperthermia treatment. Using 123I-scintigraphy, thermo-stimulation (41°C, 1 h) 24 h after CMV-NIS-MSC injection resulted in a significantly increased uptake of 123I in heat-treated tumors compared with controls. Immunohistochemical staining and real-time PCR confirmed tumor-selective, temperature-dependent MSC migration. Therapeutic efficacy was significantly enhanced by combining CMV-NIS-MSC-mediated 131I therapy with regional hyperthermia. We demonstrate here for the first time that hyperthermia can significantly boost tumoral MSC recruitment, thereby significantly enhancing therapeutic efficacy of MSC-mediated NIS gene therapy.

AB - The tropism of mesenchymal stem cells (MSCs) for tumors forms the basis for their use as delivery vehicles for the tumor-specific transport of therapeutic genes, such as the theranostic sodium iodide symporter (NIS). Hyperthermia is used as an adjuvant for various tumor therapies and has been proposed to enhance leukocyte recruitment. Here, we describe the enhanced recruitment of adoptively applied NIS-expressing MSCs to tumors in response to regional hyperthermia. Hyperthermia (41°C, 1 h) of human hepatocellular carcinoma cells (HuH7) led to transiently increased production of immunomodulatory factors. MSCs showed enhanced chemotaxis to supernatants derived from heat-treated cells in a 3D live-cell tracking assay and was validated in vivo in subcutaneous HuH7 mouse xenografts. Cytomegalovirus (CMV)-NIS-MSCs were applied 6–48 h after or 24–48 h before hyperthermia treatment. Using 123I-scintigraphy, thermo-stimulation (41°C, 1 h) 24 h after CMV-NIS-MSC injection resulted in a significantly increased uptake of 123I in heat-treated tumors compared with controls. Immunohistochemical staining and real-time PCR confirmed tumor-selective, temperature-dependent MSC migration. Therapeutic efficacy was significantly enhanced by combining CMV-NIS-MSC-mediated 131I therapy with regional hyperthermia. We demonstrate here for the first time that hyperthermia can significantly boost tumoral MSC recruitment, thereby significantly enhancing therapeutic efficacy of MSC-mediated NIS gene therapy.

KW - gene therapy

KW - hepatocellular carcinoma

KW - mesenchymal stem cells

KW - regional hyperthermia

KW - sodium iodide symporter

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ER -

Regional Hyperthermia Enhances Mesenchymal Stem Cell Recruitment to Tumor Stroma: Implications for Mesenchymal Stem Cell-Based Tumor Therapy

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Keywords

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