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Cancer Immunology, Immunotherapy

, Volume 64, Issue 11, pp 1449–1460 | Cite as

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

  • Jaime F. ModianoEmail author
  • Beth A. Lindborg
  • Ron T. McElmurry
  • Mitzi Lewellen
  • Colleen L. Forster
  • Edward A. Zamora
  • Jerome Schaack
  • Donald Bellgrau
  • Timothy D. O’Brien
  • Jakub Tolar
Original Article

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.

Keywords

Mesenchymal stromal cells Cancer Animal model Tumor immunotherapy FasL 

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

Notes

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.

Compliance with ethical standards

Conflict of interest

None of the authors have conflict of interest to disclose.

Supplementary material

262_2015_1749_MOESM1_ESM.pdf (10.5 mb)
Supplementary material 1 (PDF 10802 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Jaime F. Modiano
    • 1
    • 2
    • 3
    • 4
    Email author
  • Beth A. Lindborg
    • 3
    • 5
    • 12
  • Ron T. McElmurry
    • 2
    • 6
  • Mitzi Lewellen
    • 1
    • 2
  • Colleen L. Forster
    • 7
  • Edward A. Zamora
    • 8
  • Jerome Schaack
    • 9
    • 10
  • Donald Bellgrau
    • 10
    • 11
  • Timothy D. O’Brien
    • 2
    • 3
    • 5
  • Jakub Tolar
    • 2
    • 3
    • 6
  1. 1.Department of Veterinary Clinical Sciences, College of Veterinary Medicine and Masonic Cancer CenterUniversity of MinnesotaSt. PaulUSA
  2. 2.Masonic Cancer CenterUniversity of MinnesotaMinneapolisUSA
  3. 3.Stem Cell InstituteUniversity of MinnesotaMinneapolisUSA
  4. 4.Center for ImmunologyUniversity of MinnesotaMinneapolisUSA
  5. 5.Department of Veterinary Population Medicine, College of Veterinary MedicineUniversity of MinnesotaSt. PaulUSA
  6. 6.Department of Pediatrics, School of MedicineUniversity of MinnesotaMinneapolisUSA
  7. 7.BioNet Histology Research Laboratory, Academic Health CenterUniversity of MinnesotaMinneapolisUSA
  8. 8.Microbiology, Immunology, and Cancer Biology Graduate GroupUniversity of MinnesotaMinneapolisUSA
  9. 9.Department of Microbiology, School of MedicineUniversity of ColoradoAuroraUSA
  10. 10.University of Colorado Cancer CenterAuroraUSA
  11. 11.Integrated Department of Immunology, School of MedicineUniversity of ColoradoAuroraUSA
  12. 12.BRTI Life SciencesTwo HarborsUSA

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