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

ABSTRACT: Cancer cell secretion of TGF-? 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-? signaling blockade on progression of medulloblastoma (MB), the most common pediatric brain tumor. Genetic abrogation of T-cell TGF-? 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-? signaling blockade licenses the T-cell repertoire to kill pediatric brain tumor cells.

SUBMITTER: Gate D

PROVIDER: S-EPMC4143044 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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

Gate David D Danielpour Moise M Rodriguez Javier J Kim Gi-Bum GB Levy Rachelle R Bannykh Serguei S Breunig Joshua J JJ Kaech Susan M SM Flavell Richard A RA Town Terrence T

Proceedings of the National Academy of Sciences of the United States of America 20140731 33

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 im ...[more]

PMID: 25082897

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

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

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