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01-12-2011 | Original article

Signals through 4-1BB inhibit T regulatory cells by blocking IL-9 production enhancing antitumor responses

Authors: Shannon E. Smith, Dominique B. Hoelzinger, Ana Lucia Dominguez, Jacques Van Snick, Joseph Lustgarten

Published in: Cancer Immunology, Immunotherapy | Issue 12/2011

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.

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Title: Signals through 4-1BB inhibit T regulatory cells by blocking IL-9 production enhancing antitumor responses
Authors: Shannon E. Smith
Dominique B. Hoelzinger
Ana Lucia Dominguez
Jacques Van Snick
Joseph Lustgarten
Publication date: 01-12-2011
Publisher: Springer-Verlag
Published in: Cancer Immunology, Immunotherapy / Issue 12/2011
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-011-1075-6

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