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* Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115;
Department of Pathology and
Department of Medicine, Harvard Medical School and
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115; and
¶ College of Pharmacy and Division of Life and Pharmaceutical Science and Center for Cell Signaling and Drug Discovery Research, Ewha Womans University, Seoul, Republic of Korea
Antitumor responses depend on type 1 immunity, which is severely impaired in mice deficient for the T-box expressed in T cells (T-bet) transcription factor. Both T-bet-deficient (T-bet–/–) NK and CTL show defective function, which can be overcome by strong stimuli due to the expression of eomesodermin, another member of the T-box family. The effective response from T-bet–/– mice to viral infection and tumor initiation corroborates with these findings. However, T-bet–/– animals fail to control cancer metastasis and are, therefore, highly susceptible to tumor spread. The mechanism of T-bet-dependent resistance to metastatic disease is not known. In this study, we show that T-bet plays a role in inhibiting cancer metastasis by regulating the longevity and function of NK cells. Our data demonstrate that the absence of a proper innate immune response driven by NK cells in T-bet–/– mice precludes the initiation of a potent adaptive response to tumors. Adoptive transfer of wild-type activated NK cells protects T-bet–/– animals after melanoma challenge showing that reconstitution of the NK compartment in these mice is sufficient to mediate a significant reduction in tumor burden. Transfer of T-bet–/– A-NK cells fails to do so, due to their reduced in vivo survival, inefficient lysis of cancer cells, and poor IFN-
production. Taken together, these results show for the first time an irreplaceable role for T-bet in the NK-mediated cross-talk between innate and adaptive immune responses to metastatic disease.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by National Institutes of Health Grants AI12184 (to H.C.), AI46125 (to H.C.), CA112663 (to L.H.G.), AI31541 (to L.H.G. and G.L.-V.), and Seoul Research and Business Development Program, NCC 0620380 (to E.S.H.).
2 Current address: Section of Cell and Developmental Biology, University of California, San Diego, 9500 Gilman Drive, Natural Sciences Building 6104, La Jolla, CA 92093.
3 Address correspondence and reprint requests to Dr. Harvey I. Cantor, Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115. E-mail address: Harvey_Cantor{at}dfci.harvard.edu or Dr. Laurie H. Glimcher, Department of Immunology and Infectious Diseases, Harvard School of Public Health, 651 Huntington Avenue, François-Xavier Baqnoud building, Boston, MA 02115. E-mail address: lglimche{at}hsph.harvard.edu
4 Abbreviations used in this paper: Tc, T cytotoxic; DKO, double knockout; Dox, doxicycline; Tet, tetracycline; rtTA, reverse Tet-controlled transcriptional activator; TRE, Tet-responsive element; MCMV, murine CMV; h, human; WT, wild type; DC, dendritic cell; Eomes, eomesodermin; CMTMR, 5-(and-6)-{[(4-chloromethyl)benzoyl]amino}tetramethylrhodamine.
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