Article abstract
Nature Medicine 15, 528 - 536 (2009)
Published online: 26 April 2009 | Corrected online: 7 July 2009 | doi:10.1038/nm.1953
There is a Corrigendum (July 2009) associated with this Article.
Adjuvant IL-7 antagonizes multiple cellular and molecular inhibitory networks to enhance immunotherapies
Marc Pellegrini1,2,7, Thomas Calzascia1,2,7, Alisha R Elford1, Arda Shahinian1, Amy E Lin1,2, Dilan Dissanayake1,2, Salim Dhanji1,2, Linh T Nguyen1,2, Matthew A Gronski3, Michel Morre4, Brigitte Assouline4, Katharina Lahl5, Tim Sparwasser5,6, Pamela S Ohashi1,2,7 & Tak W Mak1,2,7
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-
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.
- The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada.
- Department of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario, Canada.
- Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia, USA.
- Cytheris Incorporated, Issy les Moulineaux, France.
- Institute for Medical Microbiology, Immunology, and Hygiene, Technische Universität München, Munich, Germany.
- Institute for Infection Immunology, Centre for Experimental and Clinical Infection Research, Hanover, Germany.
- These authors contributed equally to this work.
Correspondence to: Pamela S Ohashi1,2,7 e-mail: pohashi@uhnres.utoronto.ca
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