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Proc Natl Acad Sci U S A. 2014 Aug 19;111(33):E3458-66. doi: 10.1073/pnas.1412489111. Epub 2014 Jul 31.

T-cell TGF-β signaling abrogation restricts medulloblastoma progression.

Author information

1
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;
2
Department of Neurosurgery and Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048;
3
Department of Physiology and Biophysics, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089;
4
Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048;
5
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.
6
Department of Immunobiology andHoward Hughes Medical Institute, Yale University, New Haven, CT 06519.
7
Department of Immunobiology andHoward Hughes Medical Institute, Yale University, New Haven, CT 06519 richard.flavell@yale.edu ttown@usc.edu.
8
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.

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.

KEYWORDS:

cancer immunology; neuro-oncology; neuroimmunology

PMID:
25082897
PMCID:
PMC4143044
DOI:
10.1073/pnas.1412489111
[Indexed for MEDLINE]
Free PMC Article
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