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Adjuvant IL-7 antagonizes multiple cellular and molecular inhibitory networks to enhance immunotherapies

Nature Medicine volume 15, pages 528–536 (2009)Cite this article

A Corrigendum to this article was published on 01 July 2009

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Abstract

Identifying key factors that enhance immune responses is crucial for manipulating immunity to tumors. We show that after a vaccine-induced immune response, adjuvant interleukin-7 (IL-7) improves antitumor responses and survival in an animal model. The improved immune response is associated with increased IL-6 production and augmented T helper type 17 cell differentiation. Furthermore, IL-7 modulates the expression of two ubiquitin ligases: Casitas B-lineage lymphoma b (Cbl-b), a negative regulator of T cell activation, is repressed, and SMAD-specific E3 ubiquitin protein ligase-2 (Smurf2) is enhanced, which antagonizes transforming growth factor-β signaling. Notably, we show that although short term IL-7 therapy potently enhances vaccine-mediated immunity, in the absence of vaccination it is inefficient in promoting antitumor immune responses, despite inducing homeostatic proliferation of T cells. The ability of adjuvant IL-7 to antagonize inhibitory networks at the cellular and molecular level has major implications for immunotherapy in the treatment of tumors.

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Figure 1: IL-7 prolongs survival, decreases tumor burden and enhances tumor T cell infiltration in vaccinated mice.
Figure 2: IL-7 enhances T cell effector function and NK cell numbers.
Figure 3: Serum cytokine levels in naive and LCMV-infected mice treated with PBS or IL-7.
Figure 4: IL-7 antagonizes inhibitory pathways and modulates Smurf2, Nedd4 and Cbl-b.
Figure 5: The presence of TH17 cells, the depletion of Treg cells or the absence of Cbl-b in T cells promotes an antitumor immune response.
Figure 6: IL-7 therapy enhances antitumor immune responses in DC and vaccinia vaccination models.

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Change history

  • 07 July 2009

    In the version of this article initially published, the two right histological sections in Figure 5a were duplicated in Figure 5b. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

E. Deenick and R. Kalaf assisted with the injection of mice. M. Nikpour assisted with statistical analyses. This work was supported by a Canadian Institute for Health Research grant and funding from the Ontario Institute for Cancer Research to P.S.O. and a Terry Fox Cancer Foundation National Cancer Institute of Canada grant to T.W.M. T.C. was supported by the Boninchi Foundation (Geneva, Switzerland) and is a Research Fellow of The Terry Fox Foundation through an award from the National Cancer Institute of Canada. M.P. holds an Irvington Institute Fellowship with the Cancer Research Institute (New York). P.S.O. holds a Canada Research Chair in autoimmunity and tumor immunity.

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Author notes

  1. Marc Pellegrini, Thomas Calzascia, Pamela S Ohashi and Tak W Mak: These authors contributed equally to this work.

Authors and Affiliations

  1. The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada

    Marc Pellegrini, Thomas Calzascia, Alisha R Elford, Arda Shahinian, Amy E Lin, Dilan Dissanayake, Salim Dhanji, Linh T Nguyen, Pamela S Ohashi & Tak W Mak

  2. Department of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario, Canada

    Marc Pellegrini, Thomas Calzascia, Amy E Lin, Dilan Dissanayake, Salim Dhanji, Linh T Nguyen, Pamela S Ohashi & Tak W Mak

  3. Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia, USA

    Matthew A Gronski

  4. Cytheris Incorporated, Issy les Moulineaux, France

    Michel Morre & Brigitte Assouline

  5. Institute for Medical Microbiology, Immunology, and Hygiene, Technische Universität München, Munich, Germany

    Katharina Lahl & Tim Sparwasser

  6. Institute for Infection Immunology, Centre for Experimental and Clinical Infection Research, Hanover, Germany

    Tim Sparwasser

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Contributions

M.P. and T.C. directed the project, designed and performed experiments, interpreted data and wrote the manuscript. P.S.O. and T.W.M. directed the project, assisted with experimental design, interpreted data and contributed to the preparation of the manuscript. A.R.E., A.S., A.E.L., D.D., S.D., L.T.N. and M.A.G. assisted with experiments. M.M., B.A., K.L. and T.S. provided reagents and contributed conceptually to the project.

Corresponding author

Correspondence to Pamela S Ohashi.

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Competing interests

M.M. is the founder and chief executive officer and B.A. is an employee of Cytheris; both M.M. and B.A. have financial interest in its capital.

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Pellegrini, M., Calzascia, T., Elford, A. et al. Adjuvant IL-7 antagonizes multiple cellular and molecular inhibitory networks to enhance immunotherapies. Nat Med 15, 528–536 (2009). https://doi.org/10.1038/nm.1953

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