Identification of an indispensable role for tyrosine kinase 2 in CTL-mediated tumor surveillance

Cancer Res. 2009 Jan 1;69(1):203-11. doi: 10.1158/0008-5472.CAN-08-1705.

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.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Epitopes, T-Lymphocyte / immunology
  • Female
  • Immunologic Surveillance
  • Interferon Type I / immunology
  • Interferon-gamma / immunology
  • Interleukin-12 / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Receptor, Interferon alpha-beta / metabolism
  • Signal Transduction
  • T-Lymphocytes, Cytotoxic / enzymology*
  • T-Lymphocytes, Cytotoxic / immunology*
  • TYK2 Kinase / deficiency
  • TYK2 Kinase / genetics
  • TYK2 Kinase / immunology*
  • TYK2 Kinase / metabolism
  • Thymoma / enzymology
  • Thymoma / immunology*
  • Thymus Neoplasms / enzymology
  • Thymus Neoplasms / immunology*

Substances

  • Epitopes, T-Lymphocyte
  • Ifnar1 protein, mouse
  • Interferon Type I
  • Receptor, Interferon alpha-beta
  • Interleukin-12
  • Interferon-gamma
  • TYK2 Kinase
  • Tyk2 protein, mouse