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Mesenchymal stromal cells inhibit murine syngeneic anti-tumor immune responses by attenuating inflammation and reorganizing the tumor microenvironment

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Abstract

The potential of mesenchymal stromal cells (MSCs) to inhibit anti-tumor immunity is becoming increasingly well recognized, but the precise steps affected by these cells during the development of an anti-tumor immune response remain incompletely understood. Here, we examined how MSCs affect the steps required to mount an effective anti-tumor immune response following administration of adenovirus Fas ligand (Ad-FasL) in the Lewis lung carcinoma (LL3) model. Administration of bone marrow-derived MSCs with LL3 cells accelerated tumor growth significantly. MSCs inhibited the inflammation induced by Ad-FasL in the primary tumors, precluding their rejection; MSCs also reduced the consequent expansion of tumor-specific T cells in the treated hosts. When immune T cells were transferred to adoptive recipients, MSCs impaired, but did not completely abrogate the ability of these T cells to promote elimination of secondary tumors. This impairment was associated with a modest reduction in tumor-infiltrating T cells, with a significant reduction in tumor-infiltrating macrophages, and with a reorganization of the stromal environment. Our data indicate that MSCs in the tumor environment reduce the efficacy of immunotherapy by creating a functional and anatomic barrier that impairs inflammation, T cell priming and expansion, and T cell function—including recruitment of effector cells.

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Abbreviations

Ad:

Adenovirus

APC:

Antigen-presenting cell

CCL:

Chemokine C–C motif

FasL:

Fas ligand

GFP:

Green fluorescent protein

IFN:

Interferon

IHC:

Immunohistochemistry

IL:

Interleukin

iNOS:

Inducible nitrous oxide synthase

LL3:

Lewis lung carcinoma cells

LL3-G/L:

Lewis lung carcinoma cells expressing green fluorescent protein and luciferase

Luc:

Luciferase

MSC:

Mesenchymal stromal cell

MTS:

(3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium)

Treg:

Regulatory T cell

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Acknowledgments

The authors thank Dr. Aric Frantz, Dr. Daisuke Ito, and Lily Xia, for technical assistance and insightful suggestions. This study was supported by Grant FRD #10.03 from the University of Minnesota Academic Health Center. Histology was carried out at the Comparative Pathology Shared Resource Core of the Masonic Cancer Center and at the BioNet Histology Research Laboratory of the Academic Health Center, University of Minnesota, and was supported in part by Grant P30 CA077598 (Comprehensive Cancer Center Support Grant) from the National Institutes of Health. Edward Zamora was supported by Grant 1T32 CA009138-31s, Cancer Biology Training Grant Minority Supplement. Jaime Modiano is supported by the Alvin and June Perlman Chair in Animal Oncology. Jakub Tolar is supported by the Edmund Wallace and Anna Marie Tulloch Chair in Stem Cell Biology, Genetics, and Genomics.

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Author notes

  1. Beth A. Lindborg

    Present address: BRTI Life Sciences, Two Harbors, MN, USA

Authors and Affiliations

  1. Department of Veterinary Clinical Sciences, College of Veterinary Medicine and Masonic Cancer Center, University of Minnesota, 1365 Gortner Avenue, St. Paul, MN, 55108, USA

    Jaime F. Modiano & Mitzi Lewellen

  2. Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA

    Jaime F. Modiano, Ron T. McElmurry, Mitzi Lewellen, Timothy D. O’Brien & Jakub Tolar

  3. Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA

    Jaime F. Modiano, Beth A. Lindborg, Timothy D. O’Brien & Jakub Tolar

  4. Center for Immunology, University of Minnesota, Minneapolis, MN, USA

    Jaime F. Modiano

  5. Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St. Paul, MN, USA

    Beth A. Lindborg & Timothy D. O’Brien

  6. Department of Pediatrics, School of Medicine, University of Minnesota, Minneapolis, MN, USA

    Ron T. McElmurry & Jakub Tolar

  7. BioNet Histology Research Laboratory, Academic Health Center, University of Minnesota, Minneapolis, MN, USA

    Colleen L. Forster

  8. Microbiology, Immunology, and Cancer Biology Graduate Group, University of Minnesota, Minneapolis, MN, USA

    Edward A. Zamora

  9. Department of Microbiology, School of Medicine, University of Colorado, Aurora, CO, USA

    Jerome Schaack

  10. University of Colorado Cancer Center, Aurora, CO, USA

    Jerome Schaack & Donald Bellgrau

  11. Integrated Department of Immunology, School of Medicine, University of Colorado, Aurora, CO, USA

    Donald Bellgrau

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  1. Jaime F. Modiano
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Correspondence to Jaime F. Modiano.

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Modiano, J.F., Lindborg, B.A., McElmurry, R.T. et al. Mesenchymal stromal cells inhibit murine syngeneic anti-tumor immune responses by attenuating inflammation and reorganizing the tumor microenvironment. Cancer Immunol Immunother 64, 1449–1460 (2015). https://doi.org/10.1007/s00262-015-1749-6

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