Identification Of An Indispensable Role For Tyrosine Kinase 2 In Ctl-Mediated Tumor Surveillance

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(+) cytotoxicit.y 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 IFN gamma or ILI2p35 deficiency. Accordingly, EG7-induced tumors grew faster in]IFNARI(-/-) and Tyk2(-/-) but not in IFN gamma(-/-) or H,ILI2p35(-/-) 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. [Cancer Res 2009;69(1):203-11]