TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance.
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.
Thomas
Dori A
DA
Cancer Biology and Genetics Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Massagué
Joan
J
D051696:Activating Transcription Factors / Q000378:metabolism; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053804:Granzymes; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000502:physiology; D051379:Mice; D012697:Serine Endopeptidases / Q000378:metabolism; D051785:Smad Proteins / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*; D019139:Tumor Escape
D051696:Activating Transcription Factors; D001798:Blood Proteins; D007376:Interleukin-2; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases