title: Accessory cells of the microenvironment protect multiple myeloma from T-cell cytotoxicity through cell adhesion-mediated immune resistance.
abstract: OBJECTIVE
  Cellular immunotherapy frequently fails to induce sustained remissions in patients with multiple myeloma, indicating the ability of multiple myeloma cells to evade cellular immunity. Toward a better understanding and effective therapeutic modulation of multiple myeloma immune evasion mechanisms, we here investigated the role of the tumor microenvironment in rendering multiple myeloma cells resistant to the cytotoxic machinery of T cells.
  
  
  METHODS
  Using a compartment-specific, bioluminescence imaging-based assay system, we measured the lysis of luciferase-transduced multiple myeloma cells by CD4(+) or CD8(+) CTLs in the presence versus absence of adherent accessory cells of the bone marrow microenvironment. We simultaneously determined the level of CTL activation by measuring the granzyme B release in culture supernatants.
  
  
  RESULTS
  Bone marrow stromal cells from patients with multiple myeloma and healthy individuals, as well as vascular endothelial cells, significantly inhibited the lysis of multiple myeloma cells in a cell-cell contact-dependent manner and without substantial T-cell suppression, thus showing the induction of a cell adhesion-mediated immune resistance (CAM-IR) against CTL lysis. Further analyses revealed that adhesion to accessory cells downregulated Fas and upregulated the caspase-3 inhibitor survivin in multiple myeloma cells. Reconstitution of Fas expression with bortezomib enhanced the CTL-mediated lysis of multiple myeloma cells. Repressing survivin with the small-molecule YM155 synergized with CTLs and abrogated CAM-IR in vitro and in vivo.
  
  
  CONCLUSIONS
  These results reveal the cell adhesion-mediated induction of apoptosis resistance as a novel immune escape mechanism and provide a rationale to improve the efficacy of cellular therapies by pharmacologic modulation of CAM-IR.
authors.affiliation: Authors' Affiliations: Departments of Clinical Chemistry and Hematology, Hematology, Pathology, Cell biology, Immunology, University Medical Center Utrecht, Utrecht; Xpand Biotechnology BV, Bilthoven, the Netherlands; and Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Sanne J
authors.initials: SJ
authors.lastname: de Haart
authors.forename: Niels W C J
authors.initials: NW
authors.lastname: van de Donk
authors.forename: Monique C
authors.initials: MC
authors.lastname: Minnema
authors.forename: Julie H
authors.initials: JH
authors.lastname: Huang
authors.forename: Tineke
authors.initials: T
authors.lastname: Aarts-Riemens
authors.forename: Niels
authors.initials: N
authors.lastname: Bovenschen
authors.forename: Huipin
authors.initials: H
authors.lastname: Yuan
authors.forename: Richard W J
authors.initials: RW
authors.lastname: Groen
authors.forename: Douglas W
authors.initials: DW
authors.lastname: McMillin
authors.forename: Jana
authors.initials: J
authors.lastname: Jakubikova
authors.forename: Henk M
authors.initials: HM
authors.lastname: Lokhorst
authors.forename: Anton C
authors.initials: AC
authors.lastname: Martens
authors.forename: Constantine S
authors.initials: CS
authors.lastname: Mitsiades
authors.forename: Tuna
authors.initials: T
authors.lastname: Mutis
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002448:Cell Adhesion / Q000276:immunology; D002450:Cell Communication; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D056747:Immunomodulation; D016219:Immunotherapy, Adoptive; D051379:Mice; D009101:Multiple Myeloma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D009285:Naphthoquinones / Q000627:therapeutic use; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D059016:Tumor Microenvironment / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays; D019014:fas Receptor / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D009285:Naphthoquinones; D019014:fas Receptor; C523798:sepantronium