title: Mesenchymal stromal cells inhibit murine syngeneic anti-tumor immune responses by attenuating inflammation and reorganizing the tumor microenvironment.
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.
authors.affiliation: Department of Veterinary Clinical Sciences, College of Veterinary Medicine and Masonic Cancer Center, University of Minnesota, 1365 Gortner Avenue, St. Paul, MN, 55108, USA. modiano@umn.edu.|Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA. modiano@umn.edu.|Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA. modiano@umn.edu.|Center for Immunology, University of Minnesota, Minneapolis, MN, USA. modiano@umn.edu.
authors.forename: Jaime F
authors.initials: JF
authors.lastname: Modiano
authors.affiliation: Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA.|Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St. Paul, MN, USA.|BRTI Life Sciences, Two Harbors, MN, USA.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Lindborg
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.|Department of Pediatrics, School of Medicine, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Ron T
authors.initials: RT
authors.lastname: McElmurry
authors.affiliation: Department of Veterinary Clinical Sciences, College of Veterinary Medicine and Masonic Cancer Center, University of Minnesota, 1365 Gortner Avenue, St. Paul, MN, 55108, USA.|Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Mitzi
authors.initials: M
authors.lastname: Lewellen
authors.affiliation: BioNet Histology Research Laboratory, Academic Health Center, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Colleen L
authors.initials: CL
authors.lastname: Forster
authors.affiliation: Microbiology, Immunology, and Cancer Biology Graduate Group, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Zamora
authors.affiliation: Department of Microbiology, School of Medicine, University of Colorado, Aurora, CO, USA.|University of Colorado Cancer Center, Aurora, CO, USA.
authors.forename: Jerome
authors.initials: J
authors.lastname: Schaack
authors.affiliation: University of Colorado Cancer Center, Aurora, CO, USA.|Integrated Department of Immunology, School of Medicine, University of Colorado, Aurora, CO, USA.
authors.forename: Donald
authors.initials: D
authors.lastname: Bellgrau
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.|Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA.|Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St. Paul, MN, USA.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: O'Brien
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.|Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA.|Department of Pediatrics, School of Medicine, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Jakub
authors.initials: J
authors.lastname: Tolar
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D053222:Fas Ligand Protein / Q000235:genetics / Q000502:physiology; D007249:Inflammation / Q000517:prevention & control*; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D013601:T-Lymphocytes / Q000276:immunology* / Q000502:physiology; D059016:Tumor Microenvironment
chemical_list: D053222:Fas Ligand Protein
keywords: Animal model; Cancer; FasL; Mesenchymal stromal cells; Tumor immunotherapy