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

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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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Acknowledgments

This work was supported by Grants CA 114336 and AG287510 from the National Institutes of Health and American Federation for Aging Research (AFAR) to J.L.

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Authors and Affiliations

  1. Department of Immunology, Cancer Center Scottsdale, Mayo Clinic Arizona, Mayo Clinic College of Medicine, 13400 East Shea Boulevard, Scottsdale, AZ, 85259, USA

    Shannon E. Smith, Dominique B. Hoelzinger, Ana Lucia Dominguez & Joseph Lustgarten

  2. Ludwig Institute for Cancer Research and Experimental Medicine Unit, Universite Catholique de Louvain, Brussels, Belgium

    Jacques Van Snick

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  1. Shannon E. Smith
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  2. Dominique B. Hoelzinger
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  5. Joseph Lustgarten
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Correspondence to Joseph Lustgarten.

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Smith, S.E., Hoelzinger, D.B., Dominguez, A.L. et al. Signals through 4-1BB inhibit T regulatory cells by blocking IL-9 production enhancing antitumor responses. Cancer Immunol Immunother 60, 1775–1787 (2011). https://doi.org/10.1007/s00262-011-1075-6

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  • DOI: https://doi.org/10.1007/s00262-011-1075-6

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