title: T-cell TGF-β signaling abrogation restricts medulloblastoma progression.
abstract: Cancer cell secretion of TGF-β is a potent mechanism for immune evasion. However, little is known about how central nervous system tumors guard against immune eradication. We sought to determine the impact of T-cell TGF-β signaling blockade on progression of medulloblastoma (MB), the most common pediatric brain tumor. Genetic abrogation of T-cell TGF-β signaling mitigated tumor progression in the smoothened A1 (SmoA1) transgenic MB mouse. T regulatory cells were nearly abolished and antitumor immunity was mediated by CD8 cytotoxic T lymphocytes. To define the CD8 T-cell subpopulation responsible, primed CD8 T cells were adoptively transferred into tumor-bearing immunocompromised SmoA1 recipients. This led to generation of CD8(+)/killer cell lectin-like receptor G1 high (KLRG1(hi))/IL-7R(lo) short-lived effector cells that expressed granzyme B at the tumor. These results identify a cellular immune mechanism whereby TGF-β signaling blockade licenses the T-cell repertoire to kill pediatric brain tumor cells.
authors.affiliation: Department of Physiology and Biophysics, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089;Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048;
authors.forename: David
authors.initials: D
authors.lastname: Gate
authors.affiliation: Department of Neurosurgery and Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048;
authors.forename: Moise
authors.initials: M
authors.lastname: Danielpour
authors.affiliation: Department of Physiology and Biophysics, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089;
authors.forename: Javier
authors.initials: J
authors.lastname: Rodriguez
authors.affiliation: Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048;
authors.forename: Gi-Bum
authors.initials: GB
authors.lastname: Kim
authors.affiliation: Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048;
authors.forename: Rachelle
authors.initials: R
authors.lastname: Levy
authors.affiliation: Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA 90048;Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, CA 90048; and.
authors.forename: Serguei
authors.initials: S
authors.lastname: Bannykh
authors.affiliation: Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048;
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Breunig
authors.affiliation: Department of Immunobiology andHoward Hughes Medical Institute, Yale University, New Haven, CT 06519.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Kaech
authors.affiliation: Department of Immunobiology andHoward Hughes Medical Institute, Yale University, New Haven, CT 06519 richard.flavell@yale.edu ttown@usc.edu.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.affiliation: Department of Physiology and Biophysics, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089; richard.flavell@yale.edu ttown@usc.edu.
authors.forename: Terrence
authors.initials: T
authors.lastname: Town
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D002454:Cell Differentiation; D005434:Flow Cytometry; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D016212:Transforming Growth Factor beta
keywords: cancer immunology; neuro-oncology; neuroimmunology
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