Cancer research. 2009 Jan 1. pii: 69/1/203. doi: 10.1158/0008-5472.CAN-08-1705 |
Identification of an indispensable role for tyrosine kinase 2 in CTL-mediated tumor surveillance. |
Simma O1, Zebedin E, Neugebauer N, Schellack C, Pilz A, Chang-Rodriguez S, Lingnau K, Weisz E, Putz EM, Pickl WF, Felzmann T, Müller M, Decker T, Sexl V, Stoiber D |
Abstract We showed previously that Tyk2(-/-) natural killer cells lack the ability to lyse leukemic cells. As a consequence, the animals are leukemia prone. Here, we show that the impaired tumor surveillance extends to T cells. Challenging Tyk2(-/-) mice with EL4 thymoma significantly decreased disease latency. The crucial role of Tyk2 for CTL function was further characterized using the ovalbumin-expressing EG7 cells. Tyk2(-/-) OT-1 mice developed EG7-induced tumors significantly faster compared with wild-type (wt) controls. In vivo assays confirmed the defect in CD8(+) cytotoxicity on Tyk2 deficiency and clearly linked it to type I IFN signaling. An impaired CTL activity was only observed in IFNAR1(-/-) animals but not on IFNgamma or IL12p35 deficiency. Accordingly, EG7-induced tumors grew faster in IFNAR1(-/-) and Tyk2(-/-) but not in IFNgamma(-/-) or IL12p35(-/-) mice. Adoptive transfer experiments defined a key role of Tyk2 in CTL-mediated tumor surveillance. In contrast to wt OT-1 cells, Tyk2(-/-) OT-1 T cells were incapable of controlling EG7-induced tumor growth. |
Publikations ID: 19118004 Quelle: öffnen |