TGF-β directly targets cytotoxic T cell functions during tumor evasion of immune surveillance

被引:1004
作者
Thomas, DA
Massagué, J
机构
[1] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10021 USA
[2] Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, New York, NY 10021 USA
关键词
D O I
10.1016/j.ccr.2005.10.012
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Tumors escape from immune surveillance by producing the immunosuppressive cytokine TGF-beta. However, the mechanism by which TGF-beta inhibits T cell-mediated tumor clearance in vivo is unknown. We demonstrate that TGF-beta acts on cytotoxic T lymphocytes (CTLs) to specifically inhibit the expression of five cytolytic gene products-namely, perforin, granzyme A, granzyme B, Fas ligand, and interferon gamma-which are collectively responsible for CTL-mediated tumor cytotoxicity. Repression of granzyme B and interferon-gamma involves binding of TGF-beta-activated Smad and ATF1 transcription factors to their promoter regions, indicating direct and selective regulation by the TGF-beta/Smad pathway. Neutralization of systemic TGF-beta in mice enables tumor clearance with restoration of cytotoxic gene expression in antigen-specific CTLs in vivo. We suggest that TGF-beta suppresses CTL function in vivo through an anticytotoxic program of transcriptional repression.
引用
收藏
页码:369 / 380
页数:12
相关论文
共 47 条
[1]   TGF-β signaling in cancer -: a double-edged sword [J].
Akhurst, RJ ;
Derynck, R .
TRENDS IN CELL BIOLOGY, 2001, 11 (11) :S44-S51
[2]   Phenotypic analysis of antigen-specific T lymphocytes [J].
Altman, JD ;
Moss, PAH ;
Goulder, PJR ;
Barouch, DH ;
McHeyzerWilliams, MG ;
Bell, JI ;
McMichael, AJ ;
Davis, MM .
SCIENCE, 1996, 274 (5284) :94-96
[3]   The assessment of antigen-specific CD8+T cells through the combination of MHC class I tetramer and intracellular staining [J].
Appay, V ;
Rowland-Jones, SL .
JOURNAL OF IMMUNOLOGICAL METHODS, 2002, 268 (01) :9-19
[4]   Cancer immunotherapy: A treatment for the masses [J].
Blattman, JN ;
Greenberg, PD .
SCIENCE, 2004, 305 (5681) :200-205
[5]  
Bönig H, 1999, SCAND J IMMUNOL, V50, P612
[6]   E2F4/5 and p107 as Smad cofactors linking the TGFβ receptor to c-myc repression [J].
Chen, CR ;
Kang, YB ;
Siegel, PM ;
Massagué, J .
CELL, 2002, 110 (01) :19-32
[7]   Defective repression of c-myc in breast cancer cells:: A loss at the core of the transforming growth factor β growth arrest program [J].
Chen, CR ;
Kang, YB ;
Massagué, J .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (03) :992-999
[8]   TGF-β signaling in tumor suppression and cancer progression [J].
Derynck, R ;
Akhurst, RJ ;
Balmain, A .
NATURE GENETICS, 2001, 29 (02) :117-129
[9]   Early-onset multifocal inflammation in the transforming growth factor beta 1-null mouse is lymphocyte mediated [J].
Diebold, RJ ;
Eis, MJ ;
Yin, MY ;
Ormsby, I ;
Boivin, GP ;
Darrow, BJ ;
Saffitz, JE ;
Doetschman, T .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (26) :12215-12219
[10]   Targeting the TGFβ signaling network in human neoplasia [J].
Dumont, N ;
Arteaga, CL .
CANCER CELL, 2003, 3 (06) :531-536