T-bet plays a key role in NK-mediated control of melanoma metastatic disease

Miriam B.F. Werneck, Geanncarlo Lugo-Villarino, Eun Sook Hwang, Harvey Cantor, Laurie H. Glimcher

Research output: Contribution to journalArticlepeer-review

75 Scopus citations


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-betc) 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-dcpendent 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-γ 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.

Original languageEnglish
Pages (from-to)8004-8010
Number of pages7
JournalJournal of Immunology
Issue number12
StatePublished - 2008


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