title: Gliomas promote immunosuppression through induction of B7-H1 expression in tumor-associated macrophages.
abstract: OBJECTIVE
  Gliomas are known to induce local and systemic immunosuppression, inhibiting T-cell-mediated cytotoxic responses to tumor growth. Tumor-associated macrophages are a significant component of the immune infiltrate in gliomas and may express immunosuppressive surface ligands, such as B7-H1.
  
  
  METHODS
  Tumor and peripheral blood samples from patients with glioblastoma (GBM) were analyzed by flow cytometry to evaluate the expression of B7-H1 in circulating and tumor-infiltrating macrophages. Human monocytes from healthy patients were stimulated with conditioned media from glioma cells to evaluate B7-H1 expression. Production of interleukin (IL)-10 by stimulated monocytes was measured by ELISA, and stimulation with IL-10 alone was evaluated for the ability to induce B7-H1 expression. The effect of inhibiting IL-10 and its receptor on glioma-induced B7-H1 expression in monocytes was evaluated.
  
  
  RESULTS
  Circulating monocytes in patients with GBM had significantly increased expression of B7-H1 compared with healthy control patients. Tumor-associated macrophages from matched GBM tissue had even greater B7-H1 expression. Treatment of normal monocytes with glioma-conditioned media could significantly increase B7-H1 expression. Stimulation of monocytes with conditioned media resulted in substantial production of IL-10 and upregulation of the IL-10 receptor. Stimulation of monocytes with IL-10 alone could significantly increase B7-H1 expression, sufficient to induce T-cell apoptosis when cocultured with stimulated monocytes. Inhibition of IL-10 and the IL-10 receptor could knock down the effect of glioma media on B7-H1 by more than 50%.
  
  
  CONCLUSIONS
  Gliomas can upregulate B7-H1 expression in circulating monocytes and tumor-infiltrative macrophages through modulation of autocrine/paracrine IL-10 signaling, resulting in an immunosuppressive phenotype.
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, CA 94143, USA.
authors.forename: Orin
authors.initials: O
authors.lastname: Bloch
authors.forename: Courtney A
authors.initials: CA
authors.lastname: Crane
authors.forename: Rajwant
authors.initials: R
authors.lastname: Kaur
authors.forename: Michael
authors.initials: M
authors.lastname: Safaee
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Rutkowski
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Parsa
mesh_terms: D017209:Apoptosis / Q000235:genetics; D019898:Autocrine Communication / Q000235:genetics; D060890:B7-H1 Antigen / Q000096:biosynthesis* / Q000276:immunology; D001932:Brain Neoplasms / Q000097:blood / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D005910:Glioma / Q000097:blood / Q000235:genetics* / Q000473:pathology; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D009360:Neoplastic Cells, Circulating / Q000378:metabolism; D019899:Paracrine Communication / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
chemical_list: D060890:B7-H1 Antigen; C508609:IL10 protein, human; D016753:Interleukin-10