title: Signals through 4-1BB inhibit T regulatory cells by blocking IL-9 production enhancing antitumor responses.
abstract: Previous studies from our laboratory indicate that intratumoral (i.t.) injections of CpG-ODN are the most effective adjuvant strategy to induce an antitumor immune response in tolerant BALB-neuT mice but insufficient for tumor eradication. We evaluated whether this treatment strategy could be enhanced by the presence of anti-OX40 and anti-4-1BB antibodies. Treatment with anti-4-1BB resulted in a greater antitumor response than anti-OX40. The results indicate that anti-4-1BB but not anti-OX40 inhibited the suppressive function of T regulatory cells (Tregs). Through microarray analysis we evaluated the mechanism by which anti-4-1BB inhibits iTregs using the Foxp3-GFP mice. We observed specific transcriptional differences in over 100 genes in iTregs treated with anti-4-1BB, and selected those genes that remained unaffected by exposure to anti-OX40. Interleukin 9 was transcriptionally down-regulated 28-fold by anti-4-1BB treatment, and this was matched by a significant reduction of IL-9 secretion by iTregs. Furthermore, blockade of the common γ-chain receptor resulted in the inhibition of iTreg-suppressive function. More importantly, neutralization of IL-9 plus i.t. injections of CpG-ODN induces tumor rejection in BALB-neuT and MUC-1 tolerant transgenic mice. These results indicate that IL-9 plays a role in iTreg biology during the tumor inflammatory process enhancing/promoting the suppressive function of these cells and that the blockade of IL-9 could serve as a novel strategy to modulate the function of Tregs to enhance the antitumor effect of tumor vaccines.
authors.affiliation: Department of Immunology, Cancer Center Scottsdale, Mayo Clinic Arizona, Mayo Clinic College of Medicine, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA.
authors.forename: Shannon E
authors.initials: SE
authors.lastname: Smith
authors.forename: Dominique B
authors.initials: DB
authors.lastname: Hoelzinger
authors.forename: Ana Lucia
authors.initials: AL
authors.lastname: Dominguez
authors.forename: Jacques
authors.initials: J
authors.lastname: Van Snick
authors.forename: Joseph
authors.initials: J
authors.lastname: Lustgarten
mesh_terms: D000818:Animals; D002469:Cell Separation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007167:Immunotherapy / Q000379:methods*; D016906:Interleukin-9 / Q000096:biosynthesis* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000276:immunology*; D009838:Oligodeoxyribonucleotides / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000037:antagonists & inhibitors / Q000276:immunology*
chemical_list: D016906:Interleukin-9; D009838:Oligodeoxyribonucleotides; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9