title: Effects of interleukin-1 receptor antagonist on tumor stroma in experimental uveal melanoma.
abstract: OBJECTIVE
  In contrast to many malignancies showing evidence that interleukin-1 (IL-1) promotes progression through effects on tumor vascularity and myeloid suppressor cell populations, in uveal melanoma there is evidence that IL-1 can inhibit progression.
  
  
  METHODS
  The effects of the IL-1 receptor antagonist IL-1ra against the aggressive/invasive MUM2B and the nonaggressive/noninvasive OCM1 uveal melanoma models were examined in vitro and in vivo in mouse xenografts. Vascularity and myeloid suppressor cell populations and their regulators were assessed.
  
  
  RESULTS
  In vitro, IL-1, and IL-1ra did not affect the proliferation of the uveal melanoma cells or their production of IL-1, IL-6, transforming growth factor (TGF) β, or VEGF. In vivo, IL-1ra treatment resulted in substantial growth inhibition of MUM2B tumors; less inhibition was observed against OCM1 tumors. Periodic acid-Schiff loops and CD11b⁺ macrophages within the tumor stroma decreased in vivo; CD31⁺ blood vessels were not altered. IL-1ra treatment in vivo did not affect tumor-derived IL-1, IL-6, TGF-β, or VEGF. In contrast, host IL-1β, IL-6, and tumor necrosis factor decreased. Host VEGF was not altered. Intratumoral IL-12(p40) and CXCL10, markers of host M1 polarization, increased, and intratumoral arginase and CD206, markers of myeloid-derived suppressor cells (MDSC) and M2 macrophage polarization, decreased. IL-1ra treatment in vivo also reduced splenic CD11b⁺Gr1⁺ MDSC.
  
  
  CONCLUSIONS
  IL-1 may play a role in promoting uveal melanoma progression. Inhibiting IL-1 with IL-1ra inhibits tumor growth in vivo but not in vitro. Tumor stroma is modified, myeloid suppressor cells are reduced, and M1 macrophage polarization is increased in vivo.
authors.affiliation: Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio 44195, USA. triozzp@ccf.org
authors.forename: Pierre L
authors.initials: PL
authors.lastname: Triozzi
authors.forename: Wayne
authors.initials: W
authors.lastname: Aldrich
authors.forename: Arun
authors.initials: A
authors.lastname: Singh
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D007274:Injections, Intraperitoneal; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology*; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D014604:Uveal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
chemical_list: D016207:Cytokines; D053590:Interleukin 1 Receptor Antagonist Protein; D012333:RNA, Messenger; D011994:Recombinant Proteins