NDLI: CD137 Agonist Therapy Can Reprogram Regulatory T Cells into Cytotoxic CD4+ T Cells with Antitumor Activity.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Streeck, Hendrik Brandau, Sven Akhmetzyanova, Ilseyar Zelinskyy, Gennadiy Dittmer, Ulf Malyshkina, Anna Dietze, Kirsten K. Littwitz-Salomon, Elisabeth
Description	Author Affiliation: Akhmetzyanova I ( Institute for Virology of the University Hospital in Essen, University of Duisburg-Essen, 45147 Essen, Germany); Zelinskyy G ( Institute for Virology of the University Hospital in Essen, University of Duisburg-Essen, 45147 Essen, Germany); Littwitz-Salomon E ( Institute for Virology of the University Hospital in Essen, University of Duisburg-Essen, 45147 Essen, Germany); Malyshkina A ( Institute for Virology of the University Hospital in Essen, University of Duisburg-Essen, 45147 Essen, Germany); Dietze KK ( Institute for Virology of the University Hospital in Essen, University of Duisburg-Essen, 45147 Essen, Germany); Streeck H ( Institute for Medical Biology of the University Hospital in Essen, University of Duisburg-Essen, 45122 Essen, Germany); Brandau S ( Department of Otorhinolaryngology of the University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany.); Dittmer U ( Institute for Virology of the University Hospital in Essen, University of Duisburg-Essen, 45147 Essen, Germany)
Abstract	Recent successes in immune therapeutic strategies aimed to improve control over tumor growth have sparked hope that long-lived control of cancer through stimulation of the immune system can be possible. However, the underlying immunological mechanisms that are induced by immunotherapeutic strategies are not well understood. In this study, we used the highly immunogenic Friend virus-induced FBL-3 tumor as a model to study the mechanisms of immunological tumor control by CD4(+) T cells in the course of CD137 (4-1BB) agonist immunotherapy in the absence of a CD8 T cell response. We demonstrate that treatment with a CD137 agonist resulted in complete FBL-3 tumor regression in CD8(+) T cell-deficient mice. CD137 signaling enhanced the production of proinflammatory cytokines and cytotoxic molecules in tumor-specific CD4(+) T cells. Interestingly, a subset of CD4(+)Foxp3(+) regulatory T cells was reprogrammed to eliminate immunogenic virus-induced tumor cells in response to CD137 agonist treatment. These cells expressed markers characteristic for Th cells (CD154) and produced the cytokine TNF- or the T-box transcriptional factor Eomesodermin and granzyme B without loss of Foxp3 expression. Foxp3 Eomes double-positive CD4(+) T cells were capable of eliminating immunogenic virus-induced tumor cells in vivo. Thus, our data show that tumor-induced Foxp3(+)CD4(+) T cells can be reprogrammed into cytotoxic effector cells upon therapeutic costimulatory signaling and restore antitumor immunity.
ISSN	00221767
e-ISSN	15506606
Journal	The Journal of Immunology
Issue Number	1
Volume Number	196
Language	English
Publisher	The American Association of Immunologists
Publisher Date	2016-01-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	4-1bb Ligand Therapeutic Use Antigens, Cd137 Agonists Neoplasms, Experimental Therapy T-lymphocytes, Cytotoxic Immunology T-lymphocytes, Regulatory Animals Cd40 Ligand Metabolism Cell Line, Tumor Cellular Reprogramming Cytokines Forkhead Transcription Factors Biosynthesis Granzymes Immunotherapy Lymphocyte Depletion Mice Mice, Knockout T-box Domain Proteins Transplantation Tumor Necrosis Factor-alpha Research Support, Non-u.s. Gov't Discipline Immunology
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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